Integrin receptors antagonists

ABSTRACT

The invention relates to novel compounds which bind to integrin receptors, and to the preparation thereof and the use thereof as drugs.

The invention relates to novel compounds which bind to integrin receptors, and to the preparation and use thereof.

Integrins are cell surface glycoprotein receptors which mediate interactions between identical and different cells and between cells and extracellular matrix proteins. They are involved in physiological processes such as, for example, embryogenesis, hemostasis, wound healing, immune response and formation/maintenance of tissue architecture.

Disturbances in the expression of genes of cell adhesion molecules, and disturbances of the function of receptors may contribute to the pathogenesis of many disorders such as, for example, tumors, thromboembolic events, cardiovascular disorders, pulmonary disorders, disorders of the CNS, of the kidney, of the gastrointestinal tract or inflammations.

Integrins are heterodimers each composed of α and β transmembrane subunits, which are linked noncovalently. To date, 16 different a subunits and 8 different β subunits and 24 different combinations have been identified.

Integrin α_(v)β₃, also called vitronectin receptor, mediates the adhesion to a large number of ligands—plasma proteins, extracellular matrix proteins, cell surface proteins—most of which contain the amino acid sequence RGD (Cell, 1986, 44, 517–518; Science 1987, 238, 491–497), such as, for example, vitronectin, fibrinogen, fibronectin, von Willebrand factor, thrombospondin, osteopontin, laminin, collagen, thrombin, tenascin, MMP-2, bone sialoprotein II, various viral, parasitic and bacterial proteins, natural integrin antagonists such as disintegrins, neurotoxins—mambin—and leech proteins—decorsin, ornatin—and some non-RGD ligands such as, for example, Cyr-61, PECAM (L. Piali, J. Cell Biol. 1995, 130, 451–460; Buckley, J. Cell Science 1996, 109, 437–445, J. Biol. Chem. 1998, 273, 3090–3096).

Several integrin receptors show cross—reactivity with ligands which contain the RGD motif. Thus, integrin α_(IIb)β₃, also called platelet fibrinogen receptor, recognizes fibronectin, vitronectin, thrombospondin, von Willebrand factor and fibrinogen.

Integrin α_(v)β₃ is expressed inter alia on endothelial cells, blood platelets, monocytes/macrophages, smooth muscle cells, some B cells, fibroblasts, osteoclasts and various tumor cells such as, for example, melanomas, glioblastomas, carcinomas of the lung, breast, prostate and bladder, osteosarcomas or neuroblastomas.

Increased expression is observed under various pathological conditions such as, for example, in the prothrombotic state, when there is vessel injury, tumor growth or metastasis or reperfusion and on activated cells, in particular on endothelial cells, smooth muscle cells or macrophages.

Involvement of integrin α_(v)β₃ has been demonstrated inter alia for the following pathologies:

cardiovascular disorders such as atherosclerosis, restenosis after vessel injury, and angioplasty (neointima formation, smooth muscle cell migration and proliferation) (J. Vasc. Surg. 1994, 19, 125–134; Circulation 1994, 90, 2203–2206),

acute kidney failure (Kidney Int. 1994, 46, 1050–1058; Proc. Natl. Acad. Sci. 1993, 90, 5700–5704; Kidney Int. 1995, 48, 1375–1385),

angiogenesis-associated microangiopathies such as, for example, diabetic retinopathy or rheumatoid arthritis (Ann. Rev. Physiol 1987, 49, 453–464; Int. Ophthalmol. 1987, 11, 41–50; Cell 1994, 79, 1157–1164; J. Biol. Chem. 1992, 267, 10931–10934),

arterial thrombosis,

stroke (phase II studies with ReoPro, Centocor Inc., 8th annual European Stroke Meeting),

cancers such as, for example, in tumor metastasis or in tumor growth (tumor-induced angiogenesis) (Cell 1991, 64, 327–336; Nature 1989, 339, 58–61; Science 1995, 270, 1500–1502),

osteoporosis (bone resorption after proliferation, chemotaxis and adhesion of osteoclasts to bone matrix) (FASEB J. 1993, 7, 1475–1482; Exp. Cell Res. 1991, 195, 368–375, Cell 1991, 64, 327–336),

high blood pressure, psoriasis, hyperparathyroidism, Paget's disease, malignant hypercalcemia, metastatic osteolytic lesions, inflammation, cardiac insufficiency, CHF, and for antiviral, antiparasitic or antibacterial therapy and prophylaxis (adhesion and internalization).

Because of its key role, pharmaceutical preparations which contain low molecular weight integrin α_(v)β₃ antagonists are of great therapeutic and diagnostic benefit inter alia for the indications mentioned.

Advantageous α_(v)β₃ integrin receptor antagonists bind to the integrin α_(v)β₃ receptor with increased affinity.

Particularly advantageous α_(v)β₃ integrin receptor antagonists additionally show increased selectivity for integrin α_(v)β₃ and are less effective in relation to integrin α_(IIb)β₃ by a factor of at least 10, preferably by a factor of at least 100.

A large number of compounds such as anti-α_(v)β₃ monoclonal antibodies, peptides containing the RGD binding sequence, natural RGD-containing proteins (for example disintegrins) and low molecular weight compounds have been shown to have an integrin α_(v)β₃ antagonistic effect and have demonstrated a beneficial in vivo effect (FEBS Letts 1991, 291, 50–54; J. Biol. Chem. 1990, 265, 12267–12271; J. Biol. Chem. 1994, 269, 20233–20238; J. Cell Biol 1993, 51, 206–218; J. Biol. Chem. 1987, 262, 17703–17711; Bioorg. Med. Chem. 1998, 6, 1185–1208).

Also known are α_(v)β₃ antagonists with a tricyclic molecular structure.

WO 9915508-A1, WO 9830542-A1 and WO 9701540-A1 describe dibenzocycloheptane derivatives, WO 9911626-A1 describes dibenzo[1,4]oxazepine derivatives and WO 9905107-A1 describes benzocycloheptane derivatives.

It is an object of the present invention to provide novel integrin receptor antagonists with advantageous properties.

We have found that this object is achieved by compounds of the formula I B—G—L  I

-   -   where B, G and L have the following meanings:     -   L a structural element of the formula I_(L)         —U—T  I_(L)     -   where     -   T is a COOH group or a radical which can be hydrolyzed to COOH         and     -   —U— is —(X_(L))_(a)—(CR_(L) ¹R_(L) ²)_(b)—, —CR_(L) ¹═CR_(L) ²—,         ethynylene or ═CR_(L) ¹—, where         -   a is 0 or 1,         -   b is 0, 1 or 2         -   X_(L) is CR_(L) ³R_(L) ⁴, NR_(L) ⁵, oxygen or sulfur,         -   R_(L) ¹, R_(L) ², R_(L) ³, R_(L) ⁴             -   are, independently of one another, hydrogen, —T, —OH,                 —NR_(L) ⁶R_(L) ⁷, —CO—NH₂, a halogen radical, a branched                 or unbranched, optionally substituted C₁–C₆-alkyl,                 C₂–C₆-alkenyl, C₂–C₆-alkynyl, C₃–C₇-cycloalkyl,                 —CO—NH(C₁–C₆-alkyl), —CO—N(C₁–C₆-alkyl)₂ or C₁–C₄-alkoxy                 radical, an optionally substituted C₁–C₂-alkylene-T,                 C₂-alkenylene-T or C₂-alkynylene-T radical, an                 optionally substituted aryl or arylalkyl radical or, in                 each case independently of one another, two radicals                 R_(L) ¹ and R_(L) ² or R_(L) ³ and R_(L) ⁴ or, where                 appropriate, R_(L) ¹ and R_(L) ³ together are an                 optionally substituted 3- to 7-membered saturated or                 unsaturated carbocyclic or heterocyclic system which may                 contain up to three different or identical heteroatoms                 O, N, S,         -   R_(L) ⁵, R_(L) ⁶, R_(L) ⁷             -   are, independently of one another, hydrogen, a branched                 or unbranched, optionally substituted C₁–C₆-alkyl,                 C₃–C₇-cycloalkyl, CO—O—C₁–C₆-alkyl, SO₂—C₁–C₆-alkyl or                 CO—C₁–C₆-alkyl radical or an optionally substituted                 CO—O-alkylene-aryl, SO₂-aryl, CO-aryl, SO₂-alkylene-aryl                 or CO-alkylene-aryl radical,     -   G a structural element of the formula I_(G)

-   -   where     -   the structural element G can be incorporated in both         orientations, and     -   X_(G) is nitrogen or CR_(G) ¹ in the case where structural         element G is connected to structural element L or B via X_(G) by         a single bond,         -   or         -   is carbon in the case where structural element G is             connected to structural element L via X_(G) by a double             bond,     -   Y_(G) is CO, CS, C═NR_(G) ² or CR_(G) ³R_(G) ⁴,         -   where         -   R_(G) ¹ is hydrogen, halogen, a hydroxyl group or a branched             or unbranched, optionally substituted C₁–C₆-alkyl or             C₁–C₄-alkoxy radical,         -   R_(G) ² is hydrogen, a hydroxyl group, a branched or             unbranched, optionally substituted C₁–C₆-alkyl,             C₁–C₄-alkoxy, C₃–C₇-cycloalkyl or —O—C₃–C₇-cycloalkyl             radical or an optionally substituted aryl, —O-aryl,             arylalkyl or —O-alkylene-aryl radical and         -   R_(G) ³, R_(G) ⁴             -   are, independently of one another, hydrogen or a                 branched or unbranched, optionally substituted                 C₁–C₆-alkyl, C₂–C₆-alkenyl, C₂–C₆-alkynyl or                 C₁–C₄-alkoxy radical or the two R_(G) ³ and R_(G) ⁴                 radicals together are a cyclic acetal —O—CH₂—CH₂—O— or                 —O—CH₂—O— or the two R_(G) ³ and R_(G) ⁴ radicals                 together are an optionally substituted C₃–C₇-cycloalkyl                 radical,     -   R_(G) ⁵, R_(G) ⁶, R_(G) ⁷, R_(G) ⁸         -   are, independently of one another, hydrogen, an amino or             hydroxyl group, an HN—CO—R_(G) ⁹ radical, a branched or             unbranched, optionally substituted C₁–C₆-alkyl or             C₁–C₄-alkoxy radical, an optionally substituted aryl or             arylalkyl radical or, independently of one another, in each             case two R_(G) ⁵ and R_(G) ⁶ or R_(G) ⁷ and R_(G) ⁸ radicals             together are an optionally substituted, fused-on,             unsaturated or aromatic 3- to 6-membered carbocyclic or             heterocyclic system which may contain up to three different             or identical heteroatoms O, N, S, and     -   R_(G) ⁹ is a branched or unbranched, optionally substituted         C₁–C₆-alkyl or C₁–C₄-alkoxy radical or an optionally substituted         aryl, hetaryl, arylalkyl or hetarylalkyl radical,     -   B a structural element containing at least one atom which, under         physiological conditions, can as hydrogen acceptor form hydrogen         bonds, where the distance between at least one hydrogen acceptor         atom and the structural element G along the shortest possible         route along the structural element framework is from 4 to 13         atomic bonds,     -   and the physiologically tolerated salts, prodrugs and the         enantiomerically pure or diastereomerically pure and tautomeric         forms.

T in structural element L means a COOH group or a radical which can be hydrolyzed to COOH. A radical which can be hydrolyzed to COOH means a radical which is converted into a COOH group after hydrolysis.

An example which may be mentioned of a radical T which can be hydrolyzed to COOH is the group

in which R¹ has the following meaning:

-   a) OM where M can be a metal cation such as an alkali metal cation     such as lithium, sodium, potassium, the equivalent of an alkaline     earth metal cation such as calcium, magnesium and barium or an     environmentally compatible organic ammonium ion such as, for     example, primary, secondary, tertiary or quaternary     C₁–C₄-alkylammonium or ammonium ion, such as, for example, ONa, OK     or OLi, -   b) a branched or unbranched, optionally halogen-substituted     C₁–C₈-alkoxy radical such as, for example, methoxy, ethoxy, propoxy,     1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy,     1,1-dimethylethoxy, in particular methoxy, ethoxy, 1-methylethoxy,     pentoxy, hexoxy, heptoxy, octoxy, difluoromethoxy, trifluoromethoxy,     chlorodifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy,     2,2-difluoroethoxy, 1,1,2,2-tetrafluoroethoxy,     2,2,2-trifluoroethoxy, 2-chloro-1,1,2-trifluoroethoxy or     pentafluoroethoxy -   c) a branched or unbranched, optionally halogen-substituted     C₁–C₄-alkylthio radical such as methylthio, ethylthio, propylthio,     1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio     or 1,1-dimethylethylthio radical -   d) an optionally substituted —O-alkylene-aryl radical such as, for     example, —O-benzyl -   e) R¹ also a radical —(O)_(m)—N(R¹⁸)(R¹⁹),     -   in which m is 0 or 1, and R¹⁸ and R¹⁹, which may be identical or         different, have the following meaning:     -   hydrogen,     -   a branched or unbranched, optionally substituted     -   C₁–C₆-alkyl radical such as, for example, methyl, ethyl, propyl,         1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl,         1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,         1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,         1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl,         1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl,         2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl,         1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or         1-ethyl-2-methylpropyl or the corresponding substituted         radicals, preferably methyl, ethyl, propyl, butyl or i-butyl,     -   C₂–C₆-alkenyl radical such as, for example, vinyl, 2-propenyl,         2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,         2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl,         2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl,         2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,         1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl,         3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl,         2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,         3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl,         2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl,         1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,         1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,         1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,         2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl,         2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,         2-ethyl-2-butenyl, 2-ethyl-3-butenyl,         1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and         1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl,         2-butenyl, 3-methyl-2-butenyl or 3-methyl-2-pentenyl or the         corresponding substituted radicals,     -   C₂–C₆-alkynyl radical such as, for example, ethynyl, 2-propynyl,         2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl,         3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl,         1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl,         2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl,         1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl,         2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl,         4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl,         1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,         2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl,         2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably         2-propynyl, 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl         or the corresponding substituted radicals,     -   C₃–C₈-cycloalkyl such as, for example, cyclopropyl, cyclobutyl,         cyclopentyl, cyclohexyl and cycloheptyl, cyclooctyl or the         corresponding substituted radicals,     -   or a phenyl radical, optionally substituted one or more times,         for example one to three times, by halogen, nitro, cyano,         C₁–C₄-alkyl, C₁–C₄-haloalkyl, C₁–C₄-alkoxy, C₁–C₄-haloalkoxy or         C₁–C₄-alkylthio, such as, for example, 2-fluorophenyl,         3-chlorophenyl, 4-bromophenyl, 2-methylphenyl, 3-nitrophenyl,         4-cyanophenyl, 2-trifluoromethylphenyl, 3-methoxyphenyl,         4-trifluoroethoxyphenyl, 2-methylthiophenyl, 2,4-dichlorophenyl,         2-methoxy-3-methylphenyl, 2,4-dimethoxyphenyl,         2-nitro-5-cyanophenyl, 2,6-difluorophenyl,     -   or R¹⁸ and R¹⁹ together form a C₄–C₇-alkylene chain which is         closed to a ring, is optionally substituted, for example by         C₁–C₄-alkyl, and may contain a heteroatom selected from the         group of oxygen, sulfur or nitrogen, such as, for example,         —(CH₂)₄—, —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, —(CH₂)₂—O—(CH₂)₂—,         —CH₂—S—(CH₂)₃—, —(CH₂)₂—O—(CH₂)₃—, —NH—(CH₂)₃—, —CH₂—NH—(CH₂)₂—,         —CH₂—CH═CH—CH₂—, —CH═CH—(CH₂)₃—, —CO—(CH₂)₂—CO— or         —CO—(CH₂)₃—CO—.

Preferred T radicals are —COOH, —CO—O—C₁–C₈-alkyl or —CO—O-benzyl.

The radical —U— in the structural element L is a spacer selected from the group of —(X_(L))_(a)—(CR_(L) ¹R_(L) ²)_(b)—, —CR_(L) ¹═CR_(L) ²—, ethynylene or ═CR_(L) ¹—. In the case of the ═CR_(L) ¹— radical, the structural element L is linked by a double bond to the structural element G.

X_(L) is preferably the radical CR_(L) ³R_(L) ⁴, NR_(L) ⁵, oxygen or sulfur.

Preferred —U— radicals are the radicals ═CR_(L) ¹— or —(X_(L))_(a)—(CR_(L) ¹R_(L) ²)_(b)—, where X_(L) is preferably CR_(L) ³R_(L) ⁴ (a=0 or 1) or oxygen (a=1).

Particularly preferred —U— radicals are the radicals —(X_(L))_(a)—(CR_(L) ¹R_(L) ²)_(b)—, where X_(L) is preferably CR_(L) ³R_(L) ⁴ (a=1) or oxygen (a=1).

A halogen radical for R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ in structural element L means, for example, F, Cl, Br or I, preferably F.

A branched or unbranched C₁–C₆-alkyl radical for R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ in structural element L means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1-ethyl-2-methylpropyl, preferably branched or unbranched C₁–C₄-alkyl radicals such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, particularly preferably methyl.

A branched or unbranched C₂–C₆-alkenyl radical for R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ in structural element L means, for example, vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl or 3-methyl-2-pentenyl.

A branched or unbranched C₂–C₆-alkynyl radical for R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ in structural element L means, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl, preferably ethynyl, 2-propynyl, 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl.

A branched or unbranched C₃–C₇-cycloalkyl radical for R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ in structural element L means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A branched or unbranched C₁–C₄-alkoxy radical for R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ in structural element L means, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.

The radicals —CO—NH(C₁–C₆-alkyl) and —CO—N(C₁–C₆-alkyl)₂ are respectively secondary and tertiary amides and are composed of the amide linkage and the appropriate C₁–C₆-alkyl radicals as described above for R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴.

The R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ radicals may further be a radical C₁–C₂-alkylene-T such as, for example, methylene-T or ethylene-T, C₂-alkenylene-T such as, for example, ethenylene-T or C₂-alkynylene-T such as, for example, ethynylene-T,

an aryl radical such as, for example, phenyl, 1-naphthyl or 2-naphthyl or

an arylalkyl radical such as, for example, benzyl or phenethyl

it being possible for the radicals to be substituted where appropriate.

It is also possible for, in each case independently of one another, two radicals R_(L) ¹ and R_(L) ² or R_(L) ³ and R_(L) ⁴ or, where appropriate, R_(L) ¹ and R_(L) ³ together to be an optionally substituted 3- to 7-membered saturated or unsaturated carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S.

All radicals for R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ may optionally be substituted. Unless the substituents are specified, independently of one another up to 5 substituents are suitable for the radicals R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ and all other substituted radicals in the description hereinafter, for example selected from the following group:

—NO₂, —NH₂, —OH, —CN, —COOH, —O—CH₂—COOH, halogen, a branched or unbranched, optionally substituted C₁–C₄-alkyl such as, for example, methyl, CF₃, C₂F₅ or CH₂F, —CO—O—C₁–C₄-alkyl, C₃–C₆-cycloalkyl, C₁–C₄-alkoxy, C₁–C₄-alkylthio, —NH—CO—O—C₁–C₄-alkyl, —O—CH₂—COO—C₁–C₄-alkyl, —NH—CO—C₁–C₄-alkyl, —CO—NH—C₁–C₄-alkyl, —NH—SO₂—C₁–C₄-alkyl, —SO₂—NH—C₁–C₄-alkyl, —N(C₁–C₄-alkyl)₂, —NH—C₁–C₄-alkyl or —SO₂—C₁–C₄-alkyl radical, such as, for example, —SO₂—CF₃, an optionally substituted —NH—CO-aryl, —CO—NH-aryl, —NH—CO—O-aryl, —NH—CO—O-alkylene-aryl, —NH—SO₂-aryl, —SO₂—NH-aryl, —CO—NH-benzyl, —NH—SO₂-benzyl or —SO₂—NH-benzyl radical, an optionally substituted —SO₂—NR²R³ or —CO—NR²R³ radical, where the radicals R² and R³ may, independently of one another, have the meaning of R_(L) ⁵ hereinafter, or the two radicals R² and R³ together are a 3- to 6-membered, optionally substituted, saturated, unsaturated or aromatic heterocyclic system which, in addition to the ring nitrogen, may contain up to three other different or identical heteroatoms O, N, S, and optionally two radicals substituting this heterocyclic system together are a fused-on or saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and the ring can optionally be substituted or another, optionally substituted ring can be fused onto this ring.

Unless specified, two substituents on all terminally bonded, substituted hetaryl radicals in the description may form a fused-on, 5- to 7-membered, unsaturated or aromatic carbocyclic system.

Preferred R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ radicals are, independently of one another, hydrogen, halogen, a branched or unbranched, optionally substituted C₁–C₄-alkyl, C₁–C₄-alkoxy or C₃–C₇-cycloalkyl radical or the —NR_(L) ⁶R_(L) ⁷ radical.

Particularly preferred R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ radicals are, independently of one another, hydrogen, fluorine or a branched or unbranched, optionally substituted C₁–C₄-alkyl radical, preferably methyl.

The R_(L) ⁵, R_(L) ⁶, R_(L) ⁷ radicals in the structural element L are, independently of one another, hydrogen, a branched or unbranched, optionally substituted

C₁–C₆-alkyl radical, for example as described above for R_(L) ¹,

C₃–C₇-cycloalkyl radical, for example as described above for R_(L) ¹,

CO—O—C₁–C₆-alkyl, SO₂—C₁–C₆-alkyl or CO—C₁–C₆-alkyl radical which is composed of the group CO—O, SO₂ or CO and, for example, of the C₁–C₆-alkyl radicals described above for R_(L) ¹,

or an optionally substituted CO—O—alkylene-aryl, SO₂-aryl, SO₂-alkylene-aryl or CO-alkylene-aryl radical which is composed of the group CO—O, SO₂, or CO and, for example, of the aryl or arylalkyl radicals described above for R_(L) ¹.

Preferred R_(L) ⁶ radicals in the structural element L are hydrogen, a branched or unbranched, optionally substituted C₁–C₄-alkyl, CO—O—C₁–C₄-alkyl, CO—C₁–C₄-alkyl or SO₂—C₁–C₄-alkyl radical or an optionally substituted CO—O-benzyl, SO₂-aryl, SO₂-alkylene-aryl or CO-aryl radical.

Preferred R_(L) ⁷ radicals in the structural element L are hydrogen or a branched or unbranched, optionally substituted C₁–C₄-alkyl radical.

Preferred structural elements L are composed of the preferred radicals of the structural element.

Particularly preferred structural elements L are composed of the particularly preferred radicals of the structural element.

G is a structural element of the formula I_(G)

it being possible for the structural element G to be incorporated in both orientations. The case where X_(G) is connected by a double bond to the next structural element applies only for the orientation in which the structural element G is connected via X_(G) by a double bond to structural element L. In the case of a single bond, the structural element G can be incorporated in both orientations.

In the case where structural element G is connected to structural element L or B via X_(G) by a single bond, X_(G) is nitrogen or CR_(G) ¹.

In the case where structural element G is connected to structural element L via X_(G) by a double bond, X_(G) is carbon.

Y_(G) in structural element G is CO, CS, C═NR_(G) ² or CR_(G) ³R_(G) ⁴, preferably CO, C═NR_(G) ² or CR_(G) ³R_(G) ⁴.

R_(G) ¹ in structural element G is hydrogen, halogen such as, for example, Cl, F, Br or I, a hydroxyl group or a branched or unbranched, optionally substituted C₁–C₆-alkyl, preferably C₁–C₄-alkyl or C₁–C₄-alkoxy radical, for example as described above in each case for R_(L) ¹.

Particularly preferred R_(G) ¹ radicals are hydrogen, methoxy or ethoxy.

R_(G) ² in structural element G is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C₁–C₆-alkyl, C₁–C₄-alkoxy or C₃–C₇-cycloalkyl radical, for example as described above in each case for R_(L) ¹,

an optionally substituted —O—C₃–C₇-cycloalkyl radical which is composed of an ether group and, for example, of the C₃–C₇-cycloalkyl radical described above for R_(L) ¹,

an optionally substituted aryl or arylalkyl radical, for example as described above in each case for R_(L) ¹, or

an optionally substituted —O-aryl or —O-alkylene-aryl radical which is composed of a —O— group and, for example, of the aryl or arylalkyl radicals described above for R_(L) ¹.

Branched or unbranched, optionally substituted C₁–C₆-alkyl, C₂–C₆-alkenyl, C₂–C₆-alkynyl or C₁–C₄-alkoxy radicals for R_(G) ³ or R_(G) ⁴ in structural element G mean, independently of one another, for example the corresponding radicals described above in each case for R_(L) ¹.

It is also possible for the two radicals R_(G) ³ and R_(G) ⁴ together to form a cyclic acetal such as, for example, —O—CH₂—CH₂—O— or —O—CH₂—O—.

A further possibility is for the two radicals R_(G) ³ and R_(G) ⁴ together to form an optionally substituted C₃–C₇-cycloalkyl radical.

Preferred R_(G) ³ or R_(G) ⁴ radicals are, independently of one another, hydrogen, C₁–C₄-alkyl or C₁–C₄-alkoxy.

Branched or unbranched, optionally substituted C₁–C₆-alkyl or C₁–C₄-alkoxy radicals and optionally substituted aryl or arylalkyl radicals for R_(G) ⁵ R_(G) ⁶, R_(G) ⁷ or R_(G) ⁸ in structural element G mean, independently of one another, for example the corresponding radicals described above in each case for R_(L) ¹.

It is also possible for in each case two radicals R_(G) ⁵ and R_(G) ⁶ or R_(G) ⁷ and R_(G) ⁸ independently of one another together to form an optionally substituted, fused-on, unsaturated or aromatic 3- to 6-membered carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S.

Preferred R_(G) ⁵, R_(G) ⁶, R_(G) ⁷ or R_(G) ⁸ radicals are, independently of one another, hydrogen or optionally substituted aryl radicals, preferably phenyl or arylalkyl radicals, preferably benzyl, and in each case two radicals R_(G) ⁵ and R_(G) ⁶ or R_(G) ⁷ and R_(G) ⁸ together are an optionally substituted, fused-on, unsaturated or aromatic 3- to 6-membered carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S.

With particularly preferred radicals for R_(G) ⁵, R_(G) ⁶, R_(G) ⁷ or R_(G) ⁸, independently of one another in each case-two radicals R_(G) ⁵ and R_(G) ⁶ or R_(G) ⁷ and R_(G) ⁸ together form an optionally substituted, fused-on, unsaturated or aromatic 3- to 6-membered carbocyclic or heterocyclic system selected from one of the following doubly linked structural formulae:

A branched or unbranched, optionally substituted C₁–C₆-alkyl or C₁–C₄-alkoxy radical and an optionally substituted aryl or arylalkyl radical for R_(G) ⁹ mean, for example, the corresponding radicals described above for R_(L) ¹.

A hetaryl radical for R_(G) ⁹ means, for example, radicals such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, thiadiazolyl, oxadiazolyl or triazinyl.

Substituted hetaryl radicals for R_(G) ⁹ mean, as described above generally for terminal, substituted hetaryl radicals, also fused-on derivatives of the abovementioned hetaryl radicals, such as, for example, indazole, indole, benzothiophene, benzofuran, indoline, benzimidazole, benzothiazole, benzoxazole, quinoline or isoquinoline radicals.

A hetarylalkyl radical for R_(G) ⁹ means radicals composed, for example, of the C₁–C₆-alkyl radicals described above and of the hetaryl radicals described above, such as, preferably, the radicals —CH₂-2-pyridyl, —CH₂-3-pyridyl, —CH₂-4-pyridyl, —CH₂-2-thienyl, —CH₂-3-thienyl, —CH₂-2-thiazolyl, —CH₂-4-thiazolyl, CH₂-5-thiazolyl, —CH₂—CH₂-2-pyridyl, —CH₂—CH₂-3-pyridyl, —CH₂—CH₂-4-pyridyl, —CH₂—CH₂-2-thienyl, —CH₂—CH₂-3-thienyl, —CH₂—CH₂-2-thiazolyl, —CH₂—CH₂-4-thiazolyl or —CH₂—CH₂-5-thiazolyl.

Preferred structural elements G are composed of the preferred radicals of the structural element.

Particularly preferred structural elements G are composed of the particularly preferred radicals of the structural element.

Structural element B means a structural element containing at least one atom which, under physiological conditions, can as hydrogen acceptor form hydrogen bonds, where the distance between at least one hydrogen acceptor atom and the structural element G along the shortest possible route along the structural element framework is from 4 to 13 atomic bonds. The design of the structural framework of the structural element B can be varied widely.

Examples of suitable atoms which, under physiological conditions, can as hydrogen acceptors form hydrogen bonds are atoms with Lewis base properties such as, for example, the heteroatoms nitrogen, oxygen or sulfur.

Physiological conditions mean a pH prevailing at the site in an organism where the ligands interact with the receptors. In the present case, the physiological conditions have a pH of, for example, 5 to 9.

In a preferred embodiment, the structural element B is a structural element of the formula I_(B) A—E—  I_(B) where A and E have the following meanings: a structural element selected from the group:

-   -   a 5- to 7-membered monocyclic saturated, unsaturated or aromatic         ring having 0 to 4 heteroatoms selected from the group of O, N         or S, it being possible, in each case independently of one         another, for the ring nitrogen which is present where         appropriate or all carbons to be substituted, with the proviso         that at least one heteroatom selected from the group of O, N or         S is present in the structural element A,     -   or     -   a 9- to 14-membered polycyclic saturated, unsaturated or         aromatic system having up to 6 heteroatoms selected from the         group of N, O or S, it being possible, in each case         independently of one another, for the ring nitrogen which is         present where appropriate or all carbons to be substituted, with         the proviso that at least one heteroatom selected from the group         of O, N or S is present in the structural element A,     -   or     -   a radical

-   -   where     -   Z_(A) ¹ is oxygen, sulfur or optionally substituted nitrogen and     -   Z_(A) ² is optionally substituted nitrogen, oxygen or sulfur,         and

-   E a spacer structural element which connects structural element A to     structural element G covalently, where the number of atomic bonds     along the shortest possible route along the structural element     framework E is from 4 to 12.

In a particularly preferred embodiment, the structural element A is a structural element selected from the group of structural elements of the formulae I_(A) ¹ to I_(A) ¹⁸,

-   -   where     -   m, p, q         -   are, independently of one another, 1, 2 or 3,     -   R_(A) ¹, R_(A) ²         -   are, independently of one another, hydrogen, CN, halogen, a             branched or unbranched, optionally substituted C₁–C₆-alkyl             or CO—C₁–C₆-alkyl radical or an optionally substituted aryl,             arylalkyl, hetaryl, hetarylalkyl or C₃–C₇-cycloalkyl radical             or a radical CO—O—R_(A) ¹⁴, O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR_(A)             ¹⁵R_(A) ¹⁶, CO—NR_(A) ¹⁵R_(A) ¹⁶ or SO₂NR_(A) ¹⁵R_(A) ¹⁶ or             the two R_(A) ¹ and R_(A) ² radicals together are a             fused-on, optionally substituted 5- or 6-membered,             unsaturated or aromatic carbocyclic or heterocyclic system             which may contain up to three heteroatoms selected from the             group of O, N or S,     -   R_(A) ¹³, R_(A) ¹³*         -   are, independently of one another, hydrogen, CN, halogen, a             branched or unbranched, optionally substituted C₁–C₆-alkyl             radical or an optionally substituted aryl, arylalkyl,             hetaryl, C₃–C₇-cycloalkyl radical or a CO—O—R_(A) ¹⁴,             O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶ or CO—NR_(A)             ¹⁵R_(A) ¹⁶ radical,         -   where         -   R_(A) ¹⁴ is hydrogen, a branched or unbranched, optionally             substituted C₁–C₆-alkyl, alkylene-C₁–C₄-alkoxy,             C₂–C₆-alkenyl, C₂–C₆-alkynyl or alkylene-cycloalkyl radical             or an optionally substituted C₃–C₇-cycloalkyl, aryl,             arylalkyl, hetaryl or hetarylalkyl radical,         -   R_(A) ¹⁵, R_(A) ¹⁶,             -   are, independently of one another, hydrogen, a branched                 or unbranched, optionally substituted C₁–C₆-alkyl,                 CO—C₁–C₆-alkyl, SO₂—C₁–C₆-alkyl, COO—C₁–C₆-alkyl,                 arylalkyl, COO-alkylene-aryl, SO₂-alkylene-aryl or                 hetarylalkyl radical or an optionally substituted                 C₃–C₇-cycloalkyl, aryl, CO-aryl, SO₂-aryl, hetaryl or                 CO-hetaryl radical,     -   R_(A) ³, R_(A) ⁴         -   are, independently of one another, hydrogen,             —(CH₂)_(n)—(X_(A))_(j)—R_(A) ¹², or the two radicals             together are a 3 to 8-membered, saturated, unsaturated or             aromatic N heterocyclic system which may additionally             contain two other identical or different heteroatoms O, N or             S, it being possible for the ring optionally to be             substituted or for another, optionally substituted,             saturated, unsaturated or aromatic ring to be fused onto             this ring,     -   where         -   n can be 0, 1, 2 or 3,         -   j can be 0 or 1,         -   X_(A) can be —SO₂—, —S—, —O—, —CO—, —O—CO—, —CO—O—,             —CO—N(R_(A) ¹²)—, —N(R_(A) ¹²)—CO—, —N(R_(A) ¹²)—SO₂— or             —SO₂—N(R_(A) ¹²)- and         -   R_(A) ¹² can be hydrogen, a branched or unbranched,             optionally substituted C₁–C₆-alkyl, C₁–C₄-alkoxy,             —O-alkylene-aryl or —O-aryl radical, an amino radical with             primary or, where appropriate, secondary or tertiary             substitution, an optionally C₁–C₄-alkyl- or aryl-substituted             C₂–C₆-alkynyl or C₂–C₆-alkenyl radical or a 3- to             6-membered, saturated or unsaturated heterocyclic system             which is substituted by up to three identical or different             radicals and which may contain up to three different or             identical heteroatoms O, N, S, C₃–C₇-cycloalkyl, aryl or             hetaryl radical, it being possible for two radicals together             to be a fused-on, saturated, unsaturated or aromatic             carbocyclic or heterocyclic system which may contain up to             three different or identical heteroatoms O, N, S, and the             ring may optionally be substituted, or another, optionally             substituted, saturated, unsaturated or aromatic ring may be             fused onto this ring,     -   R_(A) ⁵ is a branched or unbranched, optionally substituted         C₁–C₆-alkyl, arylalkyl, C₃–C₇-cycloalkyl or         C₁–C₆-alkyl-C₃–C₇-cycloalkyl radical or an optionally         substituted aryl radical,     -   R_(A) ⁶, R_(A) ⁶*         -   are hydrogen, a branched or unbranched, optionally             substituted C₁–C₄-alkyl, —CO—O—C₁–C₄-alkyl, arylalkyl,             —CO—O-alkylene-aryl, —CO—O-allyl, —CO—C₁–C₄-alkyl,             —CO-alkylene-aryl, C₃–C₇-cycloalkyl or —CO-allyl radical or             the two radicals R_(A) ⁶ and R_(A) ⁶* in the structural             element I_(A) ⁷ together are an optionally substituted,             saturated, unsaturated or aromatic heterocyclic system which             may, in addition to the ring nitrogen, contain up to two             further different or identical heteroatoms O, N, S,     -   R_(A) ⁷ is hydrogen, —OH, —CN, —CONH₂, a branched or unbranched,         optionally substituted C₁–C₄-alkyl, C₁–C₄-alkoxy,         C₃–C₇-cycloalkyl or —O—CO—C₁–C₄-alkyl radical, or an optionally         substituted arylalkyl, —O-alkylene-aryl, —O—CO-aryl,         —O—CO-alkylene-aryl or —O—CO-allyl radical, or the two radicals         R_(A) ⁶ and R_(A) ⁷ together are an optionally substituted,         unsaturated or aromatic heterocyclic system which may, in         addition to the ring nitrogen, contain up to two further         different or identical heteroatoms O, N, S,     -   R_(A) ⁸ is hydrogen, a branched or unbranched, optionally         substituted C₁–C₄-alkyl, CO—C₁–C₄-alkyl, SO₂—C₁–C₄-alkyl or         CO—O—C₁–C₄-alkyl radical or an optionally substituted aryl,         CO-aryl, SO₂-aryl, CO—O-aryl, CO-alkylene-aryl,         SO₂-alkylene-aryl, CO—O-alkylene-aryl or alkylene-aryl radical,     -   R_(A) ⁹, R_(A) ¹⁰         -   are, independently of one another, hydrogen, —CN, halogen, a             branched or unbranched, optionally substituted C₁–C₆-alkyl             radical or an optionally substituted aryl, arylalkyl,             hetaryl, C₃–C₇-cycloalkyl radical or a CO—O—R_(A) ¹⁴,             O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶ or CO—NR_(A)             ¹⁵R_(A) ¹⁶ radical, or the two R_(A) ⁹ and R_(A) ¹⁰ radicals             in the structural element I_(A) ¹⁴ together are a 5- to             7-membered saturated, unsaturated or aromatic carbocyclic or             heterocyclic system which may contain up to three different             or identical heteroatoms O, N, S and is optionally             substituted by up to three identical or different radicals,     -   R_(A) ¹¹ is hydrogen, —CN, halogen, a branched or unbranched,         optionally substituted C₁–C₆-alkyl radical or an optionally         substituted aryl, arylalkyl, hetaryl, C₃–C₇-cycloalkyl radical         or a CO—O—R_(A) ¹⁴, O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶ or         CO-NR_(A) ¹⁵R_(A) ¹⁶ radical,     -   R_(A) ¹⁷ in the structural element I_(A) ¹⁶ the two radicals         R_(A) ⁹ and R_(A) ¹⁷ together are a 5- to 7-membered saturated,         unsaturated or aromatic heterocyclic system which may, in         addition to the ring nitrogen, contain up to three different or         identical heteroatoms O, N, S, and is optionally substituted by         up to three identical or different radicals,     -   Z¹, Z², Z³, Z⁴         -   are, independently of one another, nitrogen, C—H, C-halogen             or a branched or unbranched, optionally substituted             C—C₁–C₄-alkyl or C—C₁–C₄-alkoxy radical,     -   Z⁵ is NR_(A) ⁸, oxygen or sulfur.

Halogen for R_(A) ¹ or R_(A) ² in the structural elements I_(A) ¹, I_(A) ², I_(A) ³ or I_(A) ¹⁷ means, independently of one another, fluorine, chlorine, bromine or iodine.

A branched or unbranched, optionally substituted C₁–C₆-alkyl radical for R_(A) ¹ or R_(A) ² means, independently of one another, for example the corresponding radicals described above for R_(L) ¹, preferably methyl or trifluoromethyl.

The branched or unbranched, optionally substituted CO—C₁–C₆-alkyl radical for R_(A) ¹ or R_(A) ² in the structural elements I_(A) ¹, I_(A) ², I_(A) ³ or I_(A) ¹⁷ is composed, for example, of the group CO and the branched or unbranched, optionally substituted C₁–C₆-alkyl radicals described above for R_(A) ¹ or R_(A) ².

Optionally substituted aryl, arylalkyl or C₃–C₇-cycloalkyl radicals for R_(A) ¹ or R_(A) ² mean, independently of one another, for example the corresponding radicals described above for R_(L) ¹.

Optionally substituted hetaryl or alkylhetaryl radicals for R_(A) ¹ or R_(A) ² in the structural elements I_(A) ¹, I_(A) ², I_(A) ³ or I_(A) ¹⁷ mean, independently of one another, for example the corresponding radicals described above for R_(G) ⁹.

The optionally substituted radicals CO—O—R_(A) ¹⁴, O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR¹⁵R_(A) ¹⁶, CO—NR_(A) ¹⁵R_(A) ¹⁶ or SO₂NR_(A) ¹⁵R_(A) ¹⁶ for R_(A) ¹ or R_(A) ² are composed, for example, of the groups CO—O, O, S, N, CO—N or SO₂—N and the radicals R_(A) ¹⁴, R_(A) ¹⁵ and R_(A) ¹⁶ which are described in detail below.

It is also possible for the two radicals R_(A) ¹ and R_(A) ² together to form a fused-on, optionally substituted, 5- or 6-membered, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three heteroatoms selected from the group of O, N, or S.

R_(A) ¹³ and R_(A) ¹³* are, independently of one another, hydrogen, CN, halogen such as, for example, fluorine, chlorine, bromine or iodine,

a branched or unbranched, optionally substituted C₁–C₆-alkyl radical as described above, for example, for R_(A) ¹ or R_(A) ², preferably methyl or trifluoromethyl or

an optionally substituted aryl, arylalkyl, hetaryl or C₃–C₇-cycloalkyl radical or a CO—O—R_(A) ¹⁴, O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶ or CO—NR_(A) ¹⁵R_(A) ¹⁶ radical as described in each case above for R_(A) ¹ or R_(A) ².

A branched or unbranched, optionally substituted C₁–C₆-alkyl, C₃–C₇-cycloalkyl, C₂–C₆-alkenyl or C₂–C₆-alkynyl radical for R_(A) ¹⁴ in structural element A means, for example, the corresponding radicals described above for R_(L) ¹.

A branched or unbranched, optionally substituted alkylene-cycloalkyl radical or alkylene-C₁–C₄-alkoxy radical for R_(A) ¹⁴ in structural element A means, for example, radicals which are composed of the branched or unbranched, optionally substituted C₁–C₆-alkyl radicals described above for R_(L) ¹ and of the optionally substituted C₃–C₇-cycloalkyl radicals or C₁–C₄-alkoxy radicals.

Optionally substituted aryl, arylalkyl, hetaryl or alkylhetaryl radicals for R_(A) ¹⁴ in structural element A mean, for example, the corresponding radicals described above for R_(A) ¹ or R_(A) ².

A branched or unbranched, optionally substituted C₁–C₆-alkyl or arylalkyl radical or an optionally substituted C₃–C₇-cycloalkyl, aryl, hetaryl or hetarylalkyl radical for R_(A) ¹⁵ or R_(A) ¹⁶ means, independently of one another, for example the corresponding radicals described above for R_(A) ¹⁴.

The branched or unbranched, optionally substituted CO—C₁–C₆-alkyl, SO₂—C₁–C₆-alkyl, COO —C₁–C₆-alkyl, COO-alkylene-aryl or SO₂-alkylene-aryl radicals or the optionally substituted CO-aryl, SO₂-aryl or CO-hetaryl radicals for R_(A) ¹⁵ or R_(A) ¹⁶ are composed, for example, of the corresponding groups —CO—, —SO₂—, —COO— and the corresponding branched or unbranched, optionally substituted C₁–C₆-alkyl or arylalkyl radicals described above or the corresponding optionally substituted aryl or hetaryl radicals.

A —(CH₂)_(n)—(X_(A))_(j)—R_(A) ¹² radical for R_(A) ³ or R_(A) ⁴ means, independently of one another, a radical composed of the corresponding radicals —(CH₂)_(n)—, (X_(A))_(i) and R_(A) ¹². In these cases, n can be 0, 1, 2 or 3 and j can be 0 or 1.

X_(A) is a doubly linked radical selected from the group of —SO₂—, —S—, —O—, —CO—, —O—CO—, —CO—O—, —CO—N(R_(A) ¹²)—, —N(R_(A) ¹²)—CO—, —N(R_(A) ¹²)—SO₂— and —SO₂—N(R_(A) ¹²)—.

R_(A) ¹² is hydrogen,

a branched or unbranched, optionally substituted C₁–C₆-alkyl or C₁–C₄-alkoxy as described above for R_(L) ¹,

an optionally substituted —O-alkylene-aryl or —O-aryl radical, where the arylalkyl and aryl radicals have, for example, the meaning described above for R_(L) ¹ and may optionally be substituted,

an amino radical with primary or, where appropriate, secondary or tertiary substitution, such as, for example, —NH₂, —NH(C₁–C₆-alkyl) or —N(C₁–C₆-alkyl)₂ or, in the case of a terminal, singly bonded radical R_(A) ¹², also for example the corresponding cyclic amines such as, for example, N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl, and in the case where heterocycles carry free amine protons, such as, for example, N-piperazinyl, the free amine protons can be replaced by conventional amine protective groups such as, for example, methyl, benzyl, boc (tert-butoxycarbonyl), z (benzyloxycarbonyl), tosyl, —SO₂—C₁–C₄-alkyl, —SO₂-phenyl or —SO₂-benzyl, an optionally C₁–C₄-alkyl- or aryl-substituted C₂–C₆-alkynyl or C₂–C₆-alkenyl radical as described above, for example, for R_(L) ¹, or a 3- to 6-membered, saturated or unsaturated heterocyclic system which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, such as, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, triazinyl.

The various radicals may form a fused-on system as generally described above.

C₃–C₇-cycloalkyl, aryl or hetaryl radical as described above, for example, for R_(A) ¹³, it being possible for two radicals together to be a fused-on, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and the ring may optionally be substituted, or another, optionally substituted, saturated, unsaturated or aromatic ring may be fused onto this ring.

R_(A) ³ and R_(A) ⁴ may also together form a 3- to 8-membered, saturated, unsaturated or aromatic N heterocyclic system which may additionally contain two other, identical or different heteroatoms O, N or S, it being possible for the ring optionally to be substituted or for another, optionally substituted, saturated, unsaturated or aromatic ring to be fused onto this ring.

R_(A) ⁵ is a branched or unbranched, optionally substituted C₁–C₆-alkyl, arylalkyl or C₃–C₇-cycloalkyl radical as described above, for example, for R_(L) ¹, or a C₁–C₆-alkyl-C₃–C₇-cycloalkyl radical which is composed, for example, of the corresponding radicals described above.

R_(A) ⁶ and R_(A) ⁶* are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C₁–C₄-alkylradical such as, for example, optionally substituted methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl,

—CO—O—C₁–C₄-alkyl or —CO—C₁–C₄-alkyl radical such as, for example, composed of the group —CO—O— or —CO— and the C₁–C₄-alkyl radicals described above,

arylalkyl radical as described above for R_(L) ¹,

—CO—O-alkylene-aryl or —CO-alkylene-aryl radical such as, for example, composed of the group —CO—O— or —CO— and the arylalkyl radicals described above,

—CO—O-allyl or —CO-allyl radical,

or C₃–C₇-cycloalkyl radical as described above, for example, for R_(L) ¹.

It is also possible for the two radicals R_(A) ⁶ and R_(A) ⁶* in structural element I_(A) ⁷ together to form an optionally substituted, saturated, unsaturated or aromatic heterocyclic system which, in addition to the ring nitrogen, may contain up to two other different or identical heteroatoms O, N, S.

R_(A) ⁷ is hydrogen, —OH, —CN, —CONH₂, a branched or unbranched, optionally substituted C₁–C₄-alkyl radical, for example as described above for R_(A) ⁶, C₁–C₄-alkoxy, arylalkyl or C₃–C₇-cycloalkyl radical, for example as described above for R_(L) ¹, a branched or unbranched, optionally substituted —O—CO—C₁–C₄-alkyl radical which is composed of the group —O—CO— and, for example, of the abovementioned C₁–C₄-alkyl radicals, or an optionally substituted —O-alkylene-aryl, —O—CO-aryl, —O—CO-alkylene-aryl or —O—CO-allyl radical which is composed of the groups —O— or —O—CO—and, for example, of the corresponding radicals described above for R_(L) ¹.

It is also possible for the two radicals R_(A) ⁶ and R_(A) ⁷ together to form an optionally substituted, unsaturated or aromatic heterocyclic system which, in addition to the ring nitrogen, may contain up to two other different or identical heteroatoms O, N, S.

A branched or unbranched, optionally substituted C₁–C₄-alkyl radical or an optionally substituted aryl or arylalkyl radical for R_(A) ⁸ in structural element A means, for example, the corresponding radicals described above for R_(A) ¹⁵, where the CO—C₁–C₄-alkyl, SO₂—C₁–C₄-alkyl, CO—O—C₁–C₄-alkyl, CO-aryl, SO₂-aryl, CO—O—aryl, CO-alkylene-aryl, SO₂-alkylene-aryl or CO—O-alkylene-aryl radicals are composed, in analogy to the other composed radicals, of the group CO, SO₂ or COO and, for example, of the corresponding C₁–C₄-alkyl, aryl or arylalkyl radicals described above for R_(A) ¹⁵, and these radicals may optionally be substituted.

Halogen for R_(A) ⁹ or R_(A) ¹⁰ means, independently of one another, fluorine, chlorine, bromine or iodine.

A branched or unbranched, optionally substituted C₁–C₆-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl or C₃–C₇-cycloalkyl radical in each case for R_(A) ⁹ or R_(A) ¹⁰ mean, independently of one another, for example the corresponding radicals described above for R_(A) ¹⁴, preferably methyl or trifluoromethyl.

A CO—O—R_(A) ¹⁴, O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶ or CO—NR_(A) ¹⁵R_(A) ¹⁶ radical in each case for R_(A) ⁹ or R_(A) ¹⁰ means, independently of one another, for example the corresponding radicals described above for R_(A) ¹³.

It is also possible for the two radicals R_(A) ⁹ and R_(A) ¹⁰ together in the structural element I_(A) ¹⁴ to form a 5- to 7-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals.

Substituents mean in this case in particular halogen, CN, a branched or unbranched, optionally substituted C₁–C₄-alkyl radical such as, for example, methyl or trifluoromethyl or the radicals O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶, CO—NR_(A) ¹⁵R_(A) ¹⁶ or —((R_(A) ⁸)HN)C═N—R_(A) ⁷.

Halogen for R_(A) ¹¹ means, for example, fluorine, chlorine, bromine or iodine.

A branched or unbranched, optionally substituted C₁–C₆-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C₃–C₇-cycloalkyl radical or a CO—O—R_(A) ¹⁴, O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶ or CO—NR_(A) ¹⁵R_(A) ¹⁶ radical for R_(A) ¹¹ means, for example, the corresponding radicals described above for R_(A) ⁹.

It is also possible for the two radicals R_(A) ⁹ and R_(A) ¹⁷ in the structural element I_(A) ¹⁶ together to form a 5- to 7-membered saturated, unsaturated or aromatic heterocyclic system which may, in addition to the ring nitrogen, contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals.

Z¹, Z², Z³, Z⁴ are, independently of one another, nitrogen, C—H, C-halogen such as, for example, C—F, C—Cl, C—Br or C—I or a branched or unbranched, optionally substituted C—C₁–C₄-alkyl radical which is composed of a carbon radical and, for example, a C₁–C₄-alkyl radical described above for R_(A) ⁶, or a branched or unbranched, optionally substituted C—C₁–C₄-alkoxy radical which is composed of a carbon radical and, for example, a C₁–C₄-alkoxy radical described above for R_(A) ⁷.

Z⁵ is oxygen, sulfur or an NR_(A) ⁸ radical.

Preferred structural elements A are composed of the preferred radicals of the structural element.

Particularly preferred structural elements A are composed of the particularly preferred radicals of the structural element.

In a preferred embodiment, the spacer structural element E means a structural element which consists of a branched or unbranched, optionally substituted and heteroatom-containing aliphatic C₂–C₃₀-hydrocarbon radical and/or of a 4- to 20-membered, optionally substituted and heteroatom-containing, aliphatic or aromatic mono- or polycyclic hydrocarbon radical.

In a particularly preferred embodiment, the spacer structural element E is composed of two to four partial structural elements selected from the group of E¹ and E² together, the partial structural elements being linked in any sequence, and E¹ and E² having the following meanings:

-   -   E¹ a partial structural element of the formula I_(E1)         —(X_(E))_(i)—(CH₂)_(c)—CR_(E) ¹R_(E)         ²—(CH₂)_(d)—(Y_(E))_(l)—  I_(E1)         and     -   E² a partial structural element of the formula I_(E2)         —(NR_(E) ³)—(CR_(E) ⁴R_(E) ⁵)_(f)—(Q_(E))_(k)—(CR_(E) ⁶R_(E)         ⁷)_(g)—(NR_(E) ⁸)_(h)—  I_(E2),     -   where         -   c, d, f, g             -   are, independently of one another, 0, 1 or 2,         -   e, h, i, k, 1,             -   are, independently of one another, 0 or 1,         -   X_(E), Q_(E)             -   are, independently of one another, CO, CO—NR_(E) ⁹, S,                 SO, SO₂, SO₂NR_(E) ⁹, CS, CS—NR_(E) ⁹, CS—O, CO—O, O—CO,                 O, ethynyl, CR_(E) ¹⁰—O—CR_(E) ¹¹, CR_(E) ¹⁰R_(E) ¹¹,                 C(═CR_(E) ¹⁰R_(E) ¹¹), CR_(E) ¹⁰═CR_(E) ¹¹, CR_(E)                 ¹⁰(OR_(E) ¹²)—CR_(E) ¹¹, CR_(E) ¹⁰—CR_(E) ¹¹(OR_(E) ¹²)                 or an optionally substituted 4- to 11-membered mono- or                 polycyclic aliphatic or aromatic hydrocarbon which may                 contain up to 6 double bonds and up to 6 heteroatoms                 selected from the group of N, O, S,         -   Y_(E) is —CO—, —NR_(E) ⁹—CO—, —SO—, —SO₂—, —NR_(E) ⁹—SO₂—,             —CS—, —NR_(E) ⁹—CS—, —O—CS— or —O—CO—         -   R_(E) ¹, R_(E) ², R_(E) ⁴, R_(E) ⁵, R_(E) ⁶, R_(E) ⁷             -   are, independently of one another, hydrogen, halogen, a                 hydroxyl group, a branched or unbranched, optionally                 substituted C₁–C₆-alkyl, C₁–C₄-alkoxy, C₂–C₆-alkenyl,                 C₂–C₆-alkynyl or alkylene-cycloalkyl radical, a                 —(CH₂)_(w)—R_(E) ¹³ radical, an optionally substituted                 C₃–C₇-cycloalkyl, aryl, arylalkyl, hetaryl,                 hetarylalkyl, O-aryl or O-alkylene-aryl radical, or,                 independently of one another, in each case two radicals                 R_(E) ¹ and R_(E) ² or R_(E) ⁴ and R_(E) ⁵ or R_(E) ⁶                 and R_(E) ⁷ together are a 3- to 7-membered, optionally                 substituted, saturated or unsaturated carbocyclic                 system,                 -   where             -   w is 0, 1, 2, 3 or 4,         -   R_(E) ³, R_(E) ⁸, R_(E) ⁹             -   are, independently of one another, hydrogen, a branched                 or unbranched, optionally substituted C₁–C₆-alkyl,                 CO—C₁–C₆-alkyl, CO—O—C₁–C₆-alkyl or SO₂—C₁–C₆-alkyl                 radical or an optionally substituted C₃–C₇-cycloalkyl,                 CO—O-alkylene-aryl, CO-alkylene-aryl, CO-aryl, SO₂-aryl,                 CO-hetaryl or SO₂-alkylene-aryl radical,         -   R_(E) ¹⁰, R_(E) ¹¹             -   are, independently of one another, hydrogen, a hydroxyl                 group, a branched or unbranched, optionally substituted                 C₁–C₆-alkyl, C₁–C₄-alkoxy, C₂–C₆-alkenyl, C₂–C₆-alkynyl                 or alkylene-cycloalkyl radical or an optionally                 substituted C₃–C₇-cycloalkyl, aryl, arylalkyl, hetaryl                 or hetarylalkyl radical,         -   R_(E) ¹² is hydrogen, a branched or unbranched, optionally             substituted C₁–C₆-alkyl, C₂–C₆-alkenyl, C₂–C₆-alkynyl or             alkylene-cycloalkyl radical or an optionally substituted             C₃–C₇-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl             radical,         -   R_(E) ¹³ is hydrogen, a hydroxyl group, a branched or             unbranched, optionally substituted C₁–C₆-alkyl,             C₁–C₄-alkoxy, -arylalkyl, —O-alkylene-aryl or —O-aryl             radical, an amino radical with primary or, where             appropriate, secondary or tertiary substitution, an             optionally C₁–C₄-alkyl- or aryl-substituted C₂–C₆-alkynyl or             C₂–C₆-alkenyl radical, a C₅–C₁₂-bicycloalkyl,             C₆–C₁₈-tricycloalkyl radical, a CO—O—R_(A) ¹⁴ radical, or a             3- to 6-membered, saturated or unsaturated heterocyclic             system which is substituted by up to three identical or             different radicals and which may contain up to three             different or identical heteroatoms O, N, S,             C₃–C₇-cycloalkyl, aryl or hetaryl radical, it being possible             for two radicals together to be a fused-on, saturated,             unsaturated or aromatic carbocyclic or heterocyclic system             which may contain up to three different or identical             heteroatoms O, N, S, and the ring may optionally be             substituted or another, optionally substituted, saturated,             unsaturated or aromatic ring may be fused onto this ring.

In an even more preferred embodiment, the spacer structural element E used is a structural element of the formula I_(E1E2) —E₂—E₁—  I_(E1E2)

An optionally substituted 4- to 11-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which may contain up to 6 double bonds and up to 6 heteroatoms selected from the group of N, O, S for Q_(E) and X_(E) mean, independently of one another, preferably optionally substituted aryl such as, for example, optionally substituted phenyl or naphthyl, optionally substituted hetaryl such as, for example, the radicals

and their substituted derivatives, or radicals of the formulae I_(E) ¹ to I_(E) ¹¹

it being possible for the radicals to be incorporated in both orientations.

Z⁶ and Z⁷ are, independently of one another, CH or nitrogen.

Z⁸ is oxygen, sulfur or NH.

Z⁹ is oxygen, sulfur or NR_(E) ¹⁶.

r and t are, independently of one another, 0, 1, 2 or 3.

s and u are, independently of one another, 0, 1 or 2.

R_(E) ¹⁴ and R_(E) ¹⁵ are, independently of one another, hydrogen, —NO₂, —NH₂, —CN, —COOH, a hydroxyl group, halogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl, C₁–C₄-alkoxy, C₂–C₆-alkenyl, C₂–C₆-alkynyl or alkylene-cycloalkyl radical or an optionally substituted cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical as described above in each case.

R_(E) ¹⁶ means, independently of one another, hydrogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl, C₁–C₆-alkoxyalkyl, C₃–C₁₂-alkynyl, CO—C₁–C₆-alkyl, CO—O—C₁–C₆-alkyl or SO₂—C₁–C₆-alkyl radical or an optionally substituted C₃–C₇-cycloalkyl, aryl, arylalkyl, CO—O—alkylene-aryl, CO-alkylene-aryl, CO-aryl, SO₂-aryl, hetaryl, CO-hetaryl or SO₂-alkylene-aryl radical, preferably hydrogen or a branched or unbranched, optionally substituted C₁–C₆-alkyl radical.

Preferred radicals for Q_(E) are the radicals CO, CO—NR_(E) ⁹, S, SO, SO₂, SO₂NR_(E) ⁹, CS, CS—NR_(E) ⁹, CS—O, CO—O, O—CO, o, ethynyl, CR_(E) ¹⁰—O—CR_(E) ¹¹, CR_(E) ¹⁰R_(E) ¹¹, C(═CR_(E) ¹⁰R_(E) ¹¹), CR_(E) ¹⁰═CR_(E) ¹¹, R_(E) ¹⁰(OR_(E) ¹²)—CR_(E) ¹¹, CR_(E) ¹⁰—CR_(E) ¹¹(OR_(E) ¹²), substituted aryl or hetaryl as described above, or the radicals of the formulae I_(E) ¹ to I_(E) ¹¹.

Particularly preferred radicals for Q_(E) are the radicals CO, CO—NR_(E) ⁹, S, SO, SO₂, SO₂NR_(E) ⁹, CS, CS—NR_(E) ⁹, CS—O, CO—O, O—CO, O, ethynyl, CR_(E) ¹⁰—O—CR_(E) ¹¹, CR_(E) ¹⁰R_(E) ¹¹, C(═CR_(E) ¹⁰R_(E) ¹¹), CR_(E) ¹⁰=CR_(E) ¹¹, CR_(E) ¹⁰(OR_(E) ¹²)—CR_(E) ¹¹, CR_(E) ¹⁰—CR_(E) ¹¹(OR_(E) ¹²), substituted aryl or hetaryl as described above, or the radicals of the formulae I_(E) ¹, I_(E) ⁴, I_(E) ⁶′ I_(E) ⁷, I_(E) ⁹ or I_(E) ¹⁰.

Preferred radicals for X_(E) are the radicals CO, CO—NR_(E) ⁹, S, SO₂NR_(E) ⁹, CS, CS—NR_(E) ⁹, CO—O, O—CO, O, ethynyl, CR_(E) ¹⁰—O—CR_(E) ¹¹, CR_(E) ¹⁰R_(E) ¹¹ or CR_(E) ¹⁰═CR_(E) ¹¹, particularly preferably CO, CO—NR_(E) ⁹, SO₂NR_(E) ⁹, O, ethynyl, CR_(E) ¹⁰—O—CR_(E) ¹¹ or CR_(E) ¹⁰R_(E) ¹¹.

Preferred radicals for R_(E) ¹ are hydrogen, fluorine, chlorine or a —(CH₂)_(w)—R_(E) ¹³ radical, where w is 0, 1, 2, 3 or 4.

Preferred radicals for R_(E) ² are hydrogen, halogen, particularly preferably chlorine or fluorine, a hydroxyl group or a branched or unbranched, optionally substituted C₁–C₆-alkyl or C₁–C₄-alkoxy radical, particularly preferably methyl or ethyl.

In a further preferred embodiment, the two radicals R_(E) ¹ and R_(E) ² together form a 3- to 7-membered, optionally substituted, saturated, unsaturated or aromatic carbocyclic system.

The preferred and particularly preferred radicals for R_(E) ⁴ and R_(E) ⁶ and for R_(E) ⁵ and R_(E) ⁷ are, independently of one another, in each case the corresponding radicals which are the same as mentioned above for R_(E) ¹ and R_(E) ².

It is once again possible, in a preferred embodiment, for the radicals R_(E) ⁴ and R_(E) ⁵ or R_(E) ⁶ and R_(E) ⁷ together to form a 3- to 7-membered, optionally substituted carbocyclic system in this case.

Preferred radicals for R_(E) ³ are hydrogen or a branched or unbranched, optionally substituted C₁–C₆-alkyl radical, particularly preferably methyl.

Preferred radicals for R_(E) ⁸ and R_(E) ⁹ are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C₁–C₄-alkyl, C₃–C₇-cycloalkyl, CO—C₁–C₄-alkyl, CO—O—alkylene-aryl, particularly preferably CO—O—benzyl, CO-alkylene-aryl, particularly preferably CO-phenyl, CO—O—C₁–C₄-alkyl, SO₂—C₁–C₄-alkyl, SO₂-aryl, particularly preferably tosyl or SO₂-alkylene-aryl radical.

Preferred radicals for R_(E) ¹⁰ and R_(E) ¹¹ are, independently of one another, hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C₁–C₆-alkyl, particularly preferably C₁–C₄-alkyl, or C₁–C₄-alkoxy radical or an optionally substituted aryl, arylalkyl, hetaryl or hetarylalkyl radical.

Preferred radicals for R_(E) ¹² are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl radical or an optionally substituted arylalkyl or hetarylalkyl radical.

A branched or unbranched C₁–C₆-alkyl radical for R_(E) ¹³ means, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1-ethyl-2-methylpropyl, preferably methyl, ethyl, propyl, butyl, isopropyl, sec-butyl and tert-butyl.

A branched or unbranched C₁–C₄-alkoxy radical for R_(E) ¹³ means, for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy, in particular methoxy, ethoxy or 1-methylethoxy.

Examples of —O-alkylene-aryl or —O-aryl radicals are —O-phenyl, —O-1-naphthyl, —O-2-naphthyl or —O-benzyl.

The C₁–C₆-alkyl and C₁–C₄-alkoxy radicals of R_(E) ¹³ may be substituted by up to five identical or different substituents as described at the outset.

Substituted —O-alkylene-aryl or —O-aryl radicals mean, for example, the abovementioned —O-alkylene-aryl or —O-aryl radicals, it being possible for the aryl moiety to be substituted by up to three identical or different substituents as described at the outset.

An amino radical with primary or, where appropriate, secondary or tertiary substitution for R_(E) ¹³ in structural element L means a primary amino radical —NH₂, a secondary amino radical —NH(R_(E) ¹³¹) or a tertiary amino radical —N(R_(E) ¹³¹)(R_(E) ¹³²), where R_(E) ¹³¹ and R_(E) ¹³² can be, independently of one another, C₁–C₄-alkyl or C₃–C₆-cycloalkyl as mentioned above, optionally substituted aryl, preferably phenyl, arylalkyl, preferably benzyl, —CO—C₁–C₄-alkyl, preferably —CO—CH₃ or —CO-aryl, preferably —CO-phenyl.

Cyclic amino radicals result in the case where R_(E) ¹³ is one of the heterocycles described below, which is bonded via the ring nitrogen.

An optionally C₁–C₄-alkyl- or aryl-substituted C₂–C₆-alkynyl or C₂–C₆-alkenyl radical for R_(E) ¹³ means, for example, C₂–C₆-alkynyl radicals such as, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl or 1-ethyl-1-methyl-2-propynyl, preferably 2-propynyl or ethynyl

or C₂–C₆-alkenyl radical, such as, for example, vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl or 1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl or vinyl, each of which may be substituted by optionally substituted C₁–C₄-alkyl radicals or aryl radicals as mentioned above, preferably phenyl, such as, preferably, phenylethynyl or phenylethenyl.

A C₅–C₁₂-bicycloalkyl radical for R_(E) ¹³ means, for example, indanyl, norbornyl or camphyl, and a C₆–C₁₈-tricycloalkyl radical means, for example, adamantyl.

The CO—O—R_(A) ¹⁴ radical is composed, as mentioned above several times, of the group CO—O and the R_(A) ¹⁴ radical described above for structural element A.

A 3- to 6-membered, saturated or unsaturated heterocyclic system which is substituted by up to three identical or different radicals and may contain up to three different or identical heteroatoms O, N, S, or C₃˜C₈-cycloalkyl, aryl or heteroaryl radical, it being possible for two radicals together to be a fused-on, 3- to 7-membered, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and the ring can optionally be substituted, or another, optionally substituted, saturated, unsaturated or aromatic ring may be fused onto this ring, for R_(E) ¹³ means, for example,

3- to 6-membered, saturated or unsaturated heterocycles which may contain up to three different or identical heteroatoms O, N, S, such as N-pyrrolidinyl, N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl, and in the case of heterocycles which have free amine protons, such as, for example, N-piperazinyl, the free amine protons may be replaced by conventional amine protective groups, such as, for example, methyl, benzyl, boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, —SO₂—C₁–C₄-alkyl, —SO₂-phenyl or —SO₂-benzyl,

C₃–C₇-cycloalkyl radicals as described above for R_(L) ¹,

aryl radicals such as, for example, phenyl, 1-naphthyl or 2-naphthyl or

hetaryl radicals such as, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 1,3,4-thiadiazol-2-yl, 1,3,4-oxadiazol-2-yl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl or triazinyl, preferably 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl, it being possible for the heterocyclic, C₃–C₇-cycloalkyl, aryl and heteroaryl radicals optionally to be substituted by up to three identical or different radicals.

Preferred substituents of the heterocyclic, C₃–C₈-cycloalkyl, aryl and hetaryl radicals for R_(E) ¹³ are C₁–C₄-alkyl, —COOH, —COOMe, —CF₃, —CN, C₁–C₄-alkoxy, —SCH₃, —O—CH₂—COOH, -phenyl, —SO₂CH₃, —NO₂, —OH, —NH₂, —N-pyrrolidinyl, —N-piperidinyl, —N-morpholinyl, —N-piperazinyl, —NH—C₁–C₄-alkyl, —N(C₁–C₄-alkyl)₂, F, Cl, Br or I.

With the hetaryl radicals it is also possible for two radicals together to form, as described above generally, a fused-on system.

Preferred substituents of the heterocyclic, C₃˜C₈-cycloalkyl, aryl and hetaryl radicals for R_(E) ¹³ in which two radicals together are a fused-on, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and the ring may optionally be substituted or another, optionally substituted ring may be fused onto this ring, are the following doubly linked structural elements:

Examples of the resulting fused cyclic systems for R_(E) ¹³ are, for example, the corresponding dioxolanyls, benzopyrrolyls, benzofuryls, benzothienyls or fluorenyls.

Preferred structural elements E are composed of the preferred radicals for structural element E.

Preferred structural elements B are composed of the preferred structural elements A and E.

The compounds of the formula I and the intermediates for their preparation may have one or more asymmetric substituted carbon atoms. The compounds may be in the form of pure enantiomers or pure diastereomers or a mixture thereof. The use of an enantiomerically pure compound as active ingredient is preferred.

The compounds of the formula I may also be in the form of physiologically tolerated salts.

The compounds of the formula I may also be in the form of prodrugs where the compounds of the formula I are released under physiological conditions. Reference may be made in this connection by way of example to group T in structural element L, which group contains some groups which can be hydrolyzed under physiological conditions to the free carboxyl group. Also suitable are derivatized structural elements B or A which release the structural element B or A under physiological conditions.

In preferred compounds of the formula I, in each case one of the three structural elements B, G or L has the preferred range, while the remaining structural elements may vary widely.

In particularly preferred compounds of the formula I, in each case two of the three structural elements B, G or L have the preferred range, while the remaining structural elements may vary widely.

In very particularly preferred compounds of the formula I, in each case all three structural elements B, G or L have the preferred range, while the remaining structural element may vary widely.

Preferred compounds of the formula I have, for example, the preferred structural element G, while the structural elements B and L may vary widely.

In particularly preferred compounds of the formula I, for example, B is replaced by the structural element A—E—, and the compounds have, for example, the preferred structural element G and the preferred structural element A, while the structural elements E and L may vary widely.

Further particularly preferred compounds have, for example, the preferred structural element G and the preferred structural element A, while the structural elements E and L may vary widely.

Very preferred compounds of the formula I in which A—E— represents B— are listed in the following table, where “compound” represents the number of an individualized compound of the formula I, and the meaning of the abbreviations of the structural elements is explained after the table.

Compound Structural elements A-E-G-L 1 2pmhs-am2-pheac-es 2 2pmhs-dibema2-phec-gs 3 2pmhs-edia2-phec-es 4 2py-25thima2-pheaz-es 5 2py-25thima2-phec-es 6 2py-35thima2-pheaz-es 7 2py-35thima2-phec-es 8 2py-42thiaz2-pheaz-es 9 2py-42thiaz2-phec-es 10 2py-aaf-pheaz-es 11 2py-aaf-phec-es 12 2py-am2-8mephec-es 13 2py-am2-8mephec-gs 14 2py-am2-8mephec-ps 15 2py-am2-deophec-es 16 2py-am2-deophec-gs 17 2py-am2-deophec-ps 18 2py-am2-pheaz-es 19 2py-am2-pheaz-ps 20 2py-am2-phec-es 21 2py-am2-phec-gs 22 2py-am2-phec-ps 23 2py-am2-thioph-es 24 2py-am2-thioph-gs 25 2py-am2-thioph-ps 26 2py-aof-pheaz-es 27 2py-aof-phec-es 28 2py-buta-pheaz-es 29 2py-buta-phec-es 30 2py-chex2-pheaz-es 31 2py-chex2-phec-es 32 2py-dibema2-23dimephec-es 33 2py-dibema2-27dimeophec-es 34 2py-dibema2-2mephec-es 35 2py-dibema2-49dimeophec-es 36 2py-dibema2-5claz-es 37 2py-dibema2-69dimeophec-es 38 2py-dibema2-69dimephec-es 39 2py-dibema2-78diclphec-es 40 2py-dibema2-78dimeophec-es 41 2py-dibema2-8mephec-es 42 2py-dibema2-8mephec-gs 43 2py-dibema2-8mephec-ps 44 2py-dibema2-8mepyaz-es 45 2py-dibema2-9clphec-es 46 2py-dibema2-benz-es 47 2py-dibema2-cl2phec-es 48 2py-dibema2-deophec-es 49 2py-dibema2-deophec-gs 50 2py-dibema2-deophec-ps 51 2py-dibema2-deothioph-es 52 2py-dibema2-dimepy-es 53 2py-dibema2-dimepyaz-es 54 2py-dibema2-dimethio-es 55 2py-dibema2-dmaphec-es 56 2py-dibema2-imon-es 57 2py-dibema2-meoaz-es 58 2py-dibema2-meophe-es 59 2py-dibema2-meophe-nes 60 2py-dibema2-meophe-f2es 61 2py-dibema2-mephe-gs 62 2py-dibema2-pheaz-es 63 2py-dibema2-pheaz-ps 64 2py-dibema2-phec-es 65 2py-dibema2-phec-gs 66 2py-dibema2-phec-ps 67 2py-dibema2-phec-pms 68 2py-dibema2-phec-ms 69 2py-dibema2-phec-mals 70 2py-dibema2-phedb-as 71 2py-dibema2-phepyra-es 72 2py-dibema2-pyphc-es 73 2py-dibema2-sulfo-es 74 2py-dibema2-thiomet-es 75 2py-dibema2-thioph-es 76 2py-dibema2-thioph-gs 77 2py-dibema2-thioph-ps 78 2py-dibema2-thioph2-es 79 2py-dibema2-thiophaz-es 80 2py-edia2-8mephec-es 81 2py-edia2-8mephec-gs 82 2py-edia2-8mephec-ps 83 2py-edia2-deophec-es 84 2py-edia2-deophec-gs 85 2py-edia2-deophec-ps 86 2py-edia2-pheaz-es 87 2py-edia2-pheaz-ps 88 2py-edia2-phec-es 89 2py-edia2-phec-gs 90 2py-edia2-phec-ps 91 2py-edia2-phec-mals 92 2py-edia2-thioph-es 93 2py-edia2-thioph-gs 94 2py-edia2-thioph-ps 95 2py-edia2-23dimephec-es 96 2py-edia2-27dimeophec-es 97 2py-edia2-2mephec-es 98 2py-edia2-49dimeophec-es 99 2py-edia2-5claz-es 100 2py-edia2-69dimeophec-es 101 2py-edia2-69dimephec-es 102 2py-edia2-78diclphec-es 103 2py-edia2-78dimeophec-es 104 2py-edia2-8mepyaz-es 105 2py-edia2-9clphec-es 106 2py-edia2-benz-es 107 2py-edia2-cl2phec-es 108 2py-edia2-deothioph-es 109 2py-edia2-dimepy-es 110 2py-edia2-dimepyaz-es 111 2py-edia2-dimethio-es 112 2py-edia2-dmaphec-es 113 2py-edia2-imon-es 114 2py-edia2-meoaz-es 115 2py-edia2-meophe-es 116 2py-edia2-meophe-nes 117 2py-edia2-meophe-f2es 118 2py-edia2-mephe-gs 119 2py-edia2-phec-pms 120 2py-edia2-phec-ms 121 2py-edia2-phedb-as 122 2py-edia2-phepyra-es 123 2py-edia2-pyphc-es 124 2py-edia2-sulfo-es 125 2py-edia2-thiomet-es 126 2py-edia2-thioph2-es 127 2py-edia2-thiophaz-es 128 2py-edia2-6pyme-pheaz-es 129 2py-edia2-6pyme-phec-es 130 2py-edia3-pheaz-es 131 2py-edia3-phec-es 132 2py-edia3-6pyme-pheaz-es 133 2py-edia3-6pyme-phec-es 134 2py-edia4-2oxaz-pheaz-es 135 2py-edia4-2oxaz-phec-es 136 2py-edia4-2thiaz-pheaz-es 137 2py-edia4-2thiaz-phec-es 138 2py-ediammebz-pheaz-es 139 2py-ediammebz-phec-es 140 2py-ediapmebz-pheaz-es 141 2py-ediapmebz-phec-es 142 2py-hexa-pheaz-es 143 2py-hexa-phec-es 144 2py-inda2-pheaz-es 145 2py-inda2-phec-es 146 2py-me25thima2-pheaz-es 147 2py-me25thima2-phec-es 148 2py-me35thima2-pheaz-es 149 2py-me35thima2-phec-es 150 2py-me42thiaz2-pheaz-es 151 2py-me42thiaz2-phec-es 152 2py-mea26pyme-pheaz-es 153 2py-mea26pyme-phec-es 154 2py-mea3-pheaz-es 155 2py-mea3-phec-es 156 2py-mea36pyme-pheaz-es 157 2py-mea36pyme-phec-es 158 2py-mea42oxaz-pheaz-es 159 2py-mea42oxaz-phec-es 160 2py-mea42thiaz-pheaz-es 161 2py-mea42thiaz-phec-es 162 2py-meammebz-pheaz-es 163 2py-meammebz-phec-es 164 2py-meapmebz-pheaz-es 165 2py-meapmebz-phec-es 166 2py-mepipe2-pheaz-es 167 2py-mepipe2-phec-es 168 2py-mepyma2-pheaz-es 169 2py-mepyma2-phec-es 170 2py-penta-8mephec-es 171 2py-penta-8mephec-gs 172 2py-penta-8mephec-ps 173 2py-penta-deophec-es 174 2py-penta-deophec-gs 175 2py-penta-deophec-ps 176 2py-penta-pheaz-es 177 2py-penta-pheaz-ps 178 2py-penta-phec-es 179 2py-penta-phec-gs 180 2py-penta-phec-ps 181 2py-penta-thioph-es 182 2py-penta-thioph-gs 183 2py-penta-thioph-ps 184 2py-pipa2-pheaz-es 185 2py-pipa2-phec-es 186 2py-pipeme2-pheaz-es 187 2py-pipeme2-phec-es 188 2py-pyma2-pheaz-es 189 2py-pyma2-phec-es 190 3pmhs-am2-pheac-es 191 3pmhs-dibema2-phec-gs 192 3pmhs-edia2-phec-es 193 4pmhs-am2-pheac-es 194 4pmhs-dibema2-phec-gs 195 4pmhs-edia2-phec-es 196 agua-am2-pheac-es 197 agua-dibema2-phec-gs 198 agua-edia2-phec-es 199 am2py-am2-8mephec-ps 200 am2py-am2-8mephec-gs 201 am2py-am2-8mephec-es 202 am2py-am2-pheac-es 203 am2py-am2-pheaz-ps 204 am2py-am2-pheaz-gs 205 am2py-am2-pheaz-es 206 am2py-am2-phec-ps 207 am2py-am2-phec-gs 208 am2py-am2-phec-es 209 am2py-am2-phec-es 210 am2py-am2-phec-gs 211 am2py-am2-thioph-ps 212 am2py-am2-thioph-gs 213 am2py-am2-thioph-es 214 am2py-mea42thiaz-8mephec-ps 215 am2py-mea42thiaz-8mephec-gs 216 am2py-mea42thiaz-8mephec-es 217 am2py-mea42thiaz-pheaz-ps 218 am2py-mea42thiaz-pheaz-gs 219 am2py-mea42thiaz-pheaz-es 220 am2py-mea42thiaz-phec-ps 221 am2py-mea42thiaz-phec-gs 222 am2py-mea42thiaz-phec-es 223 am2py-mea42thiaz-thioph-ps 224 am2py-mea42thiaz-thioph-gs 225 am2py-mea42thiaz-thioph-es 226 am4py-am2-pheac-es 227 am4py-dibema2-phec-gs 228 am4py-edia2-phec-es 229 amhyd-am2-pheac-es 230 amhyd-am2-phec-es 231 amhyd-am2-phec-gs 232 amim-am2-pheac-es 233 amim-am2-phec-es 234 amim-am2-phec-gs 235 amthiz-am2-pheac-es 236 amthiz-dibema2-phec-gs 237 amthiz-edia2-phec-es 238 amtriz-am2-pheac-es 239 amtriz-dibema2-phec-gs 240 amtriz-edia2-phec-es 241 bgua-am2-pheac-es 242 bgua-dibema2-phec-gs 243 bgua-edia2-phec-es 244 bhs-25thima2-phec-gs 245 bhs-35thima2-phec-gs 246 bhs-42thiaz2-phec-gs 247 bhs-aaf-phec-gs 248 bhs-am2-8mephec-es 249 bhs-am2-8mephec-gs 250 bhs-am2-8mephec-ps 251 bhs-am2-deophec-es 252 bhs-am2-deophec-gs 253 bhs-am2-deophec-ps 254 bhs-am2-pheaz-es 255 bhs-am2-pheaz-ps 256 bhs-am2-phec-es 257 bhs-am2-phec-gs 258 bhs-am2-phec-ps 259 bhs-am2-thioph-es 260 bhs-am2-thioph-gs 261 bhs-am2-thioph-ps 262 bhs-aof-phec-gs 263 bhs-buta-phec-gs 264 bhs-chex2-phec-gs 265 bhs-dibema2-23dimephec-es 266 bhs-dibema2-27dimeophec-es 267 bhs-dibema2-2mephec-es 268 bhs-dibema2-49dimeophec-es 269 bhs-dibema2-5claz-es 270 bhs-dibema2-69dimeophec-es 271 bhs-dibema2-69dimephec-es 272 bhs-dibema2-78diclphec-es 273 bhs-dibema2-78dimeophec-es 274 bhs-dibema2-8mephec-es 275 bhs-dibema2-8mephec-gs 276 bhs-dibema2-8mephec-ps 277 bhs-dibema2-8mepyaz-es 278 bhs-dibema2-9clphec-es 279 bhs-dibema2-benz-es 280 bhs-dibema2-cl2phec-es 281 bhs-dibema2-deophec-es 282 bhs-dibema2-deophec-gs 283 bhs-dibema2-deophec-ps 284 bhs-dibema2-deothioph-es 285 bhs-dibema2-dimepy-es 286 bhs-dibema2-dimepyaz-es 287 bhs-dibema2-dimethio-es 288 bhs-dibema2-dmaphec-es 289 bhs-dibema2-imones 290 bhs-dibema2-meoaz-es 291 bhs-dibema2-meophe-es 292 bhs-dibema2-meophe-nes 293 bhs-dibema2-meophe-f2es 294 bhs-dibema2-mephe-gs 295 bhs-dibema2-pheaz-es 296 bhs-dibema2-pheaz-ps 297 bhs-dibema2-phec-es 298 bhs-dibema2-phec-gs 299 bhs-dibema2-phec-ps 300 bhs-dibema2-phec-pms 301 bhs-dibema2-phec-ms 302 bhs-dibema2-phec-mals 303 bhs-dibema2-phedb-as 304 bhs-dibema2-phepyra-es 305 bhs-dibema2-pyphc-es 306 bhs-dibema2-sulfo-es 307 bhs-dibema2-thiomet-es 308 bhs-dibema2-thioph-es 309 bhs-dibema2-thioph-gs 310 bhs-dibema2-thioph-ps 311 bhs-dibema2-thioph2-es 312 bhs-dibema2-thiophaz-es 313 bhs-edia2-8mephec-es 314 bhs-edia2-8mephec-gs 315 bhs-edia2-8mephec-ps 316 bhs-edia2-deophec-es 317 bhs-edia2-deophec-gs 318 bhs-edia2-deophec-ps 319 bhs-edia2-pheaz-es 320 bhs-edia2-pheaz-ps 321 bhs-edia2-phec-es 322 bhs-edia2-phec-gs 323 bhs-edia2-phec-ps 324 bhs-edia2-thioph-es 325 bhs-edia2-thioph-gs 326 bhs-edia2-thioph-ps 327 bhs-edia2-6pyme-phec-gs 328 bhs-edia3-phec-gs 329 bhs-edia3-6pyme-phec-gs 330 bhs-edia42oxaz-phec-gs 331 bhs-edia42thiaz-phec-gs 332 bhs-ediammebz-phec-gs 333 bhs-ediapmebz-phec-gs 334 bhs-hexa-phec-gs 335 bhs-inda2-phec-gs 336 bhs-me25thima2-phec-gs 337 bhs-me35thima2-phec-gs 338 bhs-me42thiaz2-phec-gs 339 bhs-mea26pyme-phec-gs 340 bhs-mea3phec-gs 341 bhs-mea36pyme-phec-gs 342 bhs-mea42oxaz-phec-gs 343 bhs-mea42thiaz-phec-gs 344 bhs-meammebz-phec-gs 345 bhs-meapmebz-phec-gs 346 bhs-mepipe2-phec-gs 347 bhs-mepyma2-phec-gs 348 bhs-penta-8mephec-es 349 bhs-penta-8mephec-gs 350 bhs-penta-8mephec-ps 351 bhs-penta-deophec-es 352 bhs-penta-deophec-gs 353 bhs-penta-deophec-ps 354 bhs-penta-pheaz-es 355 bhs-penta-pheaz-ps 356 bhs-penta-phec-es 357 bhs-penta-phec-gs 358 bhs-penta-phec-ps 359 bhs-penta-thioph-es 360 bhs-penta-thioph-gs 361 bhs-penta-thioph-ps 362 bhs-pipa2-phec-gs 363 bhs-pipeme2-phec-gs 364 bhs-pyma2-phec-gs 365 bim-25thima2-pheaz-es 366 bim-35thima2-pheaz-es 367 bim-42thiaz2-pheaz-es 368 bim-aaf-pheaz-es 369 bim-am2-23dimephec-gs 370 bim-am2-27dimeophec-gs 371 bim-am2-2mephec-gs 372 bim-am2-49dimeophec-gs 373 bim-am2-69dimeophec-gs 374 bim-am2-69dimephec-gs 375 bim-am2-78diclphec-gs 376 bim-am2-78dimeophec-gs 377 bim-am2-8mephec-es 378 bim-am2-8mephec-gs 379 bim-am2-8mephec-ps 380 bim-am2-9clphec-gs 381 bim-am2-cl2phec-gs 382 bim-am2-deophec-es 383 bim-am2-deophec-gs 384 bim-am2-deophec-ps 385 bim-am2-deothioph-gs 386 bim-am2-dimepy-gs 387 bim-am2-dimethio-gs 388 bim-am2-dmaphec-gs 389 bim-am2-imon-gs 390 bim-am2-meophe-nes 391 bim-am2-meophe-f2es 392 bim-am2-mephe-gs 393 bim-am2-pheaz-es 394 bim-am2-pheaz-ps 395 bim-am2-phec-es 396 bim-am2-phec-gs 397 bim-am2-phec-ps 398 bim-am2-phec-pms 399 bim-am2-phec-ms 400 bim-am2-phec-mals 401 bim-am2-phedb-as 402 bim-am2-phepyra-gs 403 bim-am2-pyphc-gs 404 bim-am2-sulfo-gs 405 bim-am2-thiomet-gs 406 bim-am2thioph-es 407 bim-am2-thioph-gs 408 bim-am2-thioph-ps 409 bim-am2-thioph2-gs 410 bim-aof-pheaz-es 411 bim-buta-pheaz-es 412 bim-chex2-pheaz-es 413 bim-dibema2-8mephec-es 414 bim-dibema2-8mephec-gs 415 bim-dibema2-8mephec-ps 416 bim-dibema2-deophec-es 417 bim-dibema2-deophec-gs 418 bim-dibema2-deophec-ps 419 bim-dibema2-pheaz-es 420 bim-dibema2-pheaz-ps 421 bim-dibema2-phec-es 422 bim-dibema2-phec-gs 423 bim-dibema2-phec-ps 424 bim-dibema2-thioph-es 425 bim-dibema2-thioph-gs 426 bim-dibema2-thioph-ps 427 bim-edia2-8mephec-es 428 bim-edia2-8mephec-gs 429 bim-edia2-8mephec-ps 430 bim-edia2-deophec-es 431 bim-edia2-deophec-gs 432 bim-edia2-deophec-ps 433 bim-edia2-pheaz-es 434 bim-edia2-pheaz-ps 435 bim-edia2-phec-es 436 bim-edia2-phec-gs 437 bim-edia2-phec-ps 438 bim-edia2-thioph-es 439 bim-edia2-thioph-gs 440 bim-edia2-thioph-ps 441 bim-edia26pyme-pheaz-es 442 bim-edia3-pheaz-es 443 bim-edia36pyme-pheaz-es 444 bim-edia42oxaz-pheaz-es 445 bim-edia42thiaz-pheaz-es 446 bim-ediammebz-pheaz-es 447 bim-ediapmebz-pheaz-es 448 bim-hexa-pheaz-es 449 bim-inda2-pheaz-es 450 bim-me25thima2-pheaz-es 451 bim-me35thima2-pheaz-es 452 bim-me42thiaz2-pheaz-es 453 bim-mea26pyme-pheaz-es 454 bim-mea3-pheaz-es 455 bim-mea36pyme-pheaz-es 456 bim-mea42oxaz-pheaz-es 457 bim-mea42thiaz-pheaz-es 458 bim-meammebz-pheaz-es 459 bim-meapmebz-pheaz-es 460 bim-mepipe2-pheaz-es 461 bim-mepyma2-pheaz-es 462 bim-penta-8mephec-es 463 bim-penta-8mephec-gs 464 bim-penta-8mephec-ps 465 bim-penta-deophec-es 466 bim-penta-deophec-gs 467 bim-penta-deophec-ps 468 bim-penta-pheaz-es 469 bim-penta-pheaz-ps 470 bim-penta-phec-es 471 bim-penta-phec-gs 472 bim-penta-phec-ps 473 bim-penta-thioph-es 474 bim-penta-thioph-gs 475 bim-penta-thioph-ps 476 bim-pipa2-pheaz-es 477 bim-pipeme2-pheaz-es 478 bim-pyma2-pheaz-es 479 dhim-am2-pheac-es 480 dhim-dibema2-phec-gs 481 dhim-edia2-phec-es 482 dhpyrr-am2-pheac-es 483 dhpyrr-dibema2-phec-gs 484 dhpyrr-edia2-phec-es 485 dhthi-am2-pheac-es 486 dhthi-dibema2-phec-gs 487 dhthi-edia2-phec-es 488 dimethpym-am2-pheac-es 489 dimethpym-dibema2-phec-gs 490 dimethpym-edia2-phec-es 491 gua-am2-pheac-es 492 gua-dibema2-phec-gs 493 gua-edia2-phec-es 494 hs-am2-pheac-es 495 hs-dibema2-phec-gs 496 hs-edia2-phec-es 497 hts-am2-pheac-es 498 hts-dibema2-phec-gs 499 hts-edia2-phec-es 500 hyd-am2-pheac-es 501 hyd-dibema2-phec-gs 502 hyd-edia2-phec-es 503 ibhs-am2-pheac-es 504 ibhs-dibema2-phec-gs 505 ibhs-edia2-phec-es 506 im-am2-pheac-es 507 im-dibema2-phec-gs 508 im-edia2-phec-es 509 imhs-am2-pheac-es 510 imhs-dibema2-phec-gs 511 imhs-edia2-phec-es 512 impy-am2-8mephec-es 513 impy-am2-8mephec-gs 514 impy-am2-8mephec-ps 515 impy-am2-deophec-es 516 impy-am2-deophec-gs 517 impy-am2-deophec-ps 518 impy-am2-pheaz-es 519 impy-am2-pheaz-ps 520 impy-am2-phec-es 521 impy-am2-phec-gs 522 impy-am2-phec-ps 523 impy-am2-thioph-es 524 impy-am2-thioph-gs 525 impy-am2-thioph-ps 526 impy-dibema2-8mephec-es 527 impy-dibema2-8mephec-gs 528 impy-dibema2-8mephec-ps 529 impy-dibema2-deophec-es 530 impy-dibema2-deophec-gs 531 impy-dibema2-deophec-ps 532 impy-dibema2-pheaz-es 533 impy-dibema2-pheaz-ps 534 impy-dibema2-phec-es 535 impy-dibema2-phec-gs 536 impy-dibema2-phec-ps 537 impy-dibema2-thioph-es 538 impy-dibema2-thioph-gs 539 impy-dibema2-thioph-ps 540 impy-edia2-8mephec-es 541 impy-edia2-8mephec-gs 542 impy-edia2-8mephec-ps 543 impy-edia2-deophec-es 544 impy-edia2-deophec-gs 545 impy-edia2-deophec-ps 546 impy-edia2-pheaz-es 547 impy-edia2-pheaz-ps 548 impy-edia2-phec-es 549 impy-edia2-phec-gs 550 impy-edia2-phec-ps 551 impy-edia2-thioph-es 552 impy-edia2-thioph-gs 553 impy-edia2-thioph-ps 554 impy-penta-8mephec-es 555 impy-penta-8mephec-gs 556 impy-penta-8mephec-ps 557 impy-penta-deophec-es 558 impy-penta-deophec-gs 559 impy-penta-deophec-ps 560 impy-penta-pheaz-es 561 impy-penta-pheaz-ps 562 impy-penta-phec-es 563 impy-penta-phec-gs 564 impy-penta-phec-ps 565 impy-penta-thioph-es 566 impy-penta-thioph-gs 567 impy-penta-thioph-ps 568 mam2py-am2-pheac-es 569 mam2py-dibema2-phec-gs 570 mam2py-edia2-phec-es 571 nmhs-am2-pheac-es 572 nmhs-dibema2-phec-gs 573 nmhs-edia2-pheces 574 pippy-am2-pheac-es 575 pippy-am2-phec-es 576 pippy-am2-phec-gs 577 piraz-am2-pheac-es 578 piraz-am2-phec-es 579 piraz-am2-phec-gs 580 ppy-am2-pheac-es 581 ppy-dibema2-phec-gs 582 ppy-edia2-phec-es 583 sabhs-am2-pheac-es 584 sabhs-dibema2-phec-gs 585 sabhs-edia2-phec-es 586 thazep-am2-pheac-es 587 thazep-dibema2-phec-gs 588 thazep-edia2-phec-es 589 thiz-am2-pheac-es 590 thiz-dibema2-phec-gs 591 thiz-edia2-phec-es 592 thpy-am2-pheac-es 593 thpy-dibema2-phec-gs 594 thpy-edia2-phec-es 595 thpym-am2-pheac-es 596 thpym-dibema2-phec-gs 597 thpym-edia2-phec-es 598 ur-am2-pheac-es 599 ur-dibema2-phec-gs 600 ur-edia2-phec-es

In the right-hand column of the above table, each line represents a compound. The abbreviations in the right-hand column in each case represent, separated by a hyphen, a structural element A, E, G and L, where the abbreviations have the following meanings:

A = Abbreviation

2py

thpym

dhim

nmhs

bim

4pmhs

imhs

hs

bhs

sabhs

gua

bgua

2pmhs

dhpyrr

impy

ur

hyd

ibhs

3pmhs

agua

dhthi

dimethpym

thazep

hts

mam2py

ppy

thpy

im

am2py

amthiz

pippy

am4py

amim

piraz

thiz

amhyd

amtriz

E = Abbreviation

edia2

mepipe2

pyma2

am2

pipa2

inda2

25thima2

35thima2

me35thima2

me25thima2

dibema2

penta

edia3

aof

buta

hexa

aaf

mea2

42thiaz2

pipeme2

chex2

me42thiaz2

mepyma2

mea3

edia42thiaz

mea42thiaz

edia42oxaz

mea42oxaz

ediapmebz

ediammebz

meapmebz

meammebz

edia26pyme

edia36pyme

mea26pyme

mea36pyme

G = Abbreviation

2mephec

8mephec

meophe

23dimephec

9clphec

78dimeophec

69dimeophec

78diclphec

69dimephec

49dimeophec

imon

dimepy

dimethio

sulfo

pyphc

thioph

pheaz

thiomet

phepyra

benz

phec

dimepyaz

8mepyaz

meoaz

phedb

5claz

thiophaz

mephe

c12phec

27dimeophec

deophec

thioph2

deothioph

dmaphec

L = Abbreviation

es

ps

gs

ms

pms

nes

f2es

as

mals

Compounds of the general formula I and the starting materials used to prepare them can generally be prepared by methods of organic chemistry known to the skilled worker as described in standard works such as, for example, Houben-Weyl, “Methoden der Organischen Chemie”, Thieme-Verlag, Stuttgart, or March “Advanced Organic Chemistry”, 4th Edition, Wiley & Sons. Further preparation methods are also described in R. Larock, “Comprehensive organic Transformations”, weinheim 1989, in particular the preparation of alkenes, alkynes, halides, amines, ethers, alcohols, phenols, aldehydes, ketones, nitriles, carboxylic acids, esters, amides and acid chlorides.

The general synthesis of compounds of the formula I where A—E— represents B is described in schemes 1–7. Unless otherwise indicated, all the starting materials and reagents can be bought or can be prepared by conventional methods from precursors which can be bought.

Scheme 1 describes the synthesis of compounds of the formula I in general.

Building blocks of type II (for X_(L) equal to CH) are known and can be prepared by known methods starting from appropriately substituted or fused 1H-azepine-2,5-diones as described by way of example e.g. in J. Med. Chem. 1986, 29, 1877–1888 or DE 1568217. 1H-Azepine-2,5-diones used to prepare compounds of type I can either be bought or be prepared as described in the following publications:

5H-Dibenzo[b,e]azepine-6,11-dione and substituted variants according to J. Med. Chem. 1965, 8, 74 or Gazz. Chim. Ital. 1953, 83, 533 and 1954, 84, 1135;

5H-pyrido[3,2-c][1]benzazepine-5,11(6H)-dione according to Liebigs Ann. Chem. 1989, 469–476;

4H-thieno[3,2-c][1]benzazepine-4,10 (5H)-dione according to Eur. J. Med. Chem. Ther. 1981, 16, 391–398.

The conversion to III is carried out by hydrogenating the double bond under standard conditions. It is also possible for this to make use of variants which are known per se but which are not mentioned here. The hydrogenation is preferably carried out in the presence of a noble metal catalyst such as, for example, Pd on active carbon, Pt, PtO₂, Rh on Al₂O₃ in an inert solvent at a temperature of 0–150° C. under a pressure of 1–200 bar; addition of an acid such as, for example, acetic acid or hydrochloric acid may be advantageous. Hydrogenation in the presence of 5–10% Pd on active carbon is particularly preferred.

Solvents which can be used are all conventional inert solvents such as, for example, hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform, dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; ketones such as acetone, butanone; amides such as dimethylformamide (DMF), dimethylacetamide or acetamide; sulfoxides such as dimethyl sulfoxide, sulfolane; pyridine, N-methylpyrrolidone, 1,3-dimethyltetrahydro-2 (1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone, water or mixtures of said solvents.

Compounds of type IV are prepared by reaction with compounds of the general formula A—E—U_(E) (VI), where the U_(E) radical is a conventional leaving group, for example halogen such as chlorine, bromine, iodine or an optionally halogen-, alkyl- or haloalkyl-substituted aryl- or alkylsulfonyloxy radical such as, for example, toluenesulfonyloxy, trifluoromethanesulfonyloxy and methylsulfonyloxy or another equivalent leaving group.

The reaction preferably takes place in an inert solvent with the addition of a suitable base, i.e. a base which deprotonates the intermediate III, at a temperature in the range from −40° C. to the boiling point of the appropriate solvent.

The base which can be used is an alkali metal or alkaline earth metal hydride such as sodium hydride, potassium hydride or calcium hydride, a carbonate such as alkali metal carbonate, for example sodium or potassium carbonate, an alkali metal or alkaline earth metal hydroxide such as sodium or potassium hydroxide, an alcoholate such as, for example, sodium methanolate, potassium tert-butanolate, an organometallic compound such as butyllithium or alkali metal amides such as lithium diisopropylamide, lithium, sodium or potassium bis(trimethylsilyl)amide.

Elimination of the protective group SG1 under standard conditions (see below) results in the compounds of the general formula I. Where SG1 is equal to C₁–C₄-alkyl or benzyl, the compounds of the general formula IV correspond directly to the compounds of type I.

As an alternative to this synthetic strategy, compounds of type I can also be prepared via V as intermediate, in which case the reaction conditions used are those known to the skilled worker and described in standard works. Compound V is prepared by reacting compounds of type III with compounds of the general formula D_(E)—E—U_(E) (VII) under the reaction conditions already described for preparing IV. U_(E) is a suitable leaving group as described above, and DE is CN or a protected amino or acid function of the general formula NSG₃ or COOSG₂. The fragments D_(E)—E and A—E are synthesized—depending on the actual structure of E— by eliminating the protective groups and coupling on the remaining fragments by standard methods, for example amide coupling. The introduction of A then takes place in analogy to the reactions described in schemes 3–7.

Compounds of type I in which X_(G) is N can be prepared as shown in scheme 2.

The synthesis starts from compounds of type VIII which are either known or accessible to the skilled worker by known methods as described, for example, in Pharmazie 45 (8), 1990, 555–559. Alkylation with a compound of the general formula XI (U_(U)=conventional leaving group as described above for U_(E)) under the reaction conditions described for preparing substances of type IV results in IX. The subsequent reactions to I via X take place in analogy to Scheme 1.

The coupling of the individual fragments and the elimination of the protective groups can take place by known processes (see Larock, “Comprehensive organic Transformations”; protective groups: Greene and Wuts, T., “Protective Groups in Organic Synthesis”, New York 1991), and in the case of amide linkages also analogous to the methods of peptide synthesis as described in standard works, for example in Bodanszky “The Practice of Peptide Synthesis”, 2nd Edition, Springer-Verlag 1994, and Bodanszky “Principles of Peptide Synthesis”, Springer-Verlag 1984. A general review of the conventional methods for peptide synthesis and a listing of suitable reagents can moreover be found in NOVABIOCHEM 1999 “Catalog and Peptide Synthesis Handbook”.

Said amide couplings can be carried out with the aid of conventional coupling reagents using suitably protected amino and carboxylic acid derivatives. Another method comprises the use of preactivated carboxylic acid derivatives, preferably of carbonyl halides, symmetrical or mixed anhydrides or so-called active esters, which are normally used to acylate amines. These activated carboxylic acid derivatives can also be prepared in situ. The couplings can usually be carried out in inert solvents in the presence of an acid-binding agent, preferably an organic base such as, for example, triethylamine, pyridine, diisopropylethylamine, N-methylmorpholine, quinoline; it may also be beneficial to add an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another weak acid salt of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or cesium.

The reaction time is between minutes and 14 days, and the reaction temperature is between −40° C. and 140° C., preferably between −20° C. and 100° C., depending on the conditions used.

Examples of suitable inert solvents are hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; ketones such as acetone, butanone; amides such as dimethylformamide (DMF), dimethylacetamide or acetamide; nitrites such as acetonitrile; sulfoxides such as dimethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1,3-dimethyltetrahydro-2 (1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone, nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; water; or mixtures of said solvents.

The protective groups SG which can be used are all conventional protective groups known to the skilled worker from peptide synthesis, as are also described in the abovementioned standard works.

Elimination of the protective groups in the compounds of the formula IV, V, VI and VII likewise takes place under conditions known to the skilled worker and described, for example, by Greene and Wuts in “Protective Groups in Organic Synthesis”, 2nd Edition, Wiley & Sons, 1991.

Protective groups such as SG₃ are so-called N-terminal amino protective groups; those preferred for this are Boc, Fmoc, benzyloxycarbonyl (Z), acetyl or Mtr.

SG₁ and SG₂ are so-called C-terminal hydroxyl protective groups, and these are preferably C₁–C₄-alkyl such as, for example, methyl, ethyl, tert-butyl or else benzyl or trityl, or else polymer-bound protective groups in the form of the commercially available polystyrene resins such as, for example, 2-chlorotrityl chloride-resin or Wang resin (supplied by Bachem, Novabiochem).

Acid-labile protective groups (for example Boc, tert-butyl, Mtr, trityl) can be eliminated—depending on the protective group used—with organic acids such as trifluoroacetic acid (TFA), trichloroacetic acid, perchloric acid, trifluoroethanol; but also inorganic acids such as hydrochloric acid or sulfuric acid, sulfonic acids such as benzene- or p-toluenesulfonic acid, with the acids generally being employed in excess. In the case of trityl it may be advantageous to add thiols such as, for example, thioanisole or thiophenol. The presence of an additional inert solvent is possible but not always necessary. Suitable and preferred inert solvents are organic solvents, for example carboxylic acids such as acetic acid; ethers such as THF or dioxane; amides such as DMF or dimethylacetamide; halogenated hydrocarbons such as dichloromethane; alcohols such as methanol, isopropanol; or water. Mixtures of said solvents are also suitable.

The temperature for these reactions is between 10° C. and 50° C., preferably in the range between 0° C. and 30° C.

Base-labile protective groups such as fmoc are cleaved by treatment with organic amines such as dimethylamine, diethylamine, morpholine, piperidine as 5–50% solutions in CH₂Cl₂ or DMF. The temperature for these reactions is between 10° C. and 50° C., preferably in the range between 0° C. and 30° C.

Acid-protective groups such as methyl or ethyl are preferably cleaved by basic hydrolysis in an inert solvent. The bases preferably used are alkali metal or alkaline earth metal hydroxides, preferably NaOH, KOH or LiOH;

the solvents used are all conventional inert solvents such as, for example, hydrocarbons such as hexane, heptane, petroleum ether, toluene, benzene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, dioxane; glycol ethers such as ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether; ketones such as acetone, butanone; amides such as dimethylformamide (DMF), dimethylacetamide or acetamide; nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide, sulfolane; N-methylpyrrolidone, 1,3-dimethyltetrahydro-2 (1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone; nitro compounds such as nitromethane or nitrobenzene; water or mixtures of said solvents. Addition of a phase-transfer catalyst may be advantageous, depending on the solvent or mixture thereof used. The temperature for these reactions is generally between −10° C. and 100° C.

Protective groups which can be eliminated by hydrogenolysis, such as benzyloxycarbonyl (Z) or benzyl can be eliminated, for example, by hydrogenolysis in the presence of a catalyst (for example a noble metal catalyst on active carbon as support). Suitable solvents are those indicated above, in particular alcohols such as methanol, ethanol; amides such as DMF or dimethylacetamide; esters such as ethyl acetate. The hydrogenolysis is usually carried out under a pressure of from 1 to 200 bar and at temperatures between 0° C. and 100° C.; addition of an acid such as, for example, acetic acid or hydrochloric acid may be advantageous. 5 to 10% Pd on active carbon is preferably used as catalyst.

The synthesis of building blocks of type E generally takes place by methods known to the skilled worker; the building blocks used can either be bought or be obtained by methods known from the literature. The synthesis of some of these building blocks is described by way of example in the experimental section.

In the case where the fragments Q_(E) and X_(E) present in the compounds of type V and VI are a hetaryl radical, the radical E can be synthesized via compounds of type VI-VII starting from aminohetaryl carboxylic acids, aminohetaryl carboxylic esters or nitriles by described methods known to the skilled worker. A large number of preparation methods are described in detail in Houben-Weyls “Methoden der organischen Chemie” (Vol. E6: Furans, thiophenes, pyrroles, indoles, benzothiophenes, -furans, -pyrroles; Vol. E7: Quinolines, pyridines, Vol. E8: Isoxazoles, oxazoles, thiazoles, pyrazoles, imidazoles and benzo-fused representatives thereof, and oxadiazoles, thiadiazoles and triazoles; Vol. E9: Pyridazines, pyrimidines, triazines, azepines and the benzo-fused representatives thereof, and purines). The linkage of these fragments to E can also take place via the amino or acid function, depending on the structure of E, by methods known to the skilled worker.

Appropriate hetaryl derivatives can either be bought or be prepared in analogy to the following publications:

-   5-(Aminomethyl)-2-pyridinecarbonitrile according to WO 95/25426, -   5-(Aminomethyl)-3-thiophenecarbonitrile according to WO 98/06741, -   5-(Aminomethyl)-2-thiophenecarbonitrile in WO 95/23609, -   2-(Aminomethyl)-1,3-thiazole-4-carbonitrile in analogy to WO     98/06741, -   3-Oxo-5-isoindolinecarboxylic acid according to WO 97/37655, -   3-Amino-2-pyrrolidone according to WO 98/44797,     Spirocycles such as -   8-(aminomethyl)-2-oxa-3-azaspiro[4,5]dec-3-en-4-yl acetate and -   7-(aminomethyl)-2-oxa-3-azaspiro[4.4]non-3-en-4-yl acetate     according to WO 97/33887, -   [5-(2-Aminoalkyl)-4,5-dihydro-3-isoxazolyl]carboxylic acid and     acetate, [3-(2-aminoalkyl)-4,5-dihydro-5-isoxazolyl]carboxylic acid     and acetate according to WO 96/37492, -   1-(3-Aminoalkyl)-1H-indazole-5-carboxylic acid according to WO     97/23480; -   Ethyl 2-amino-1,3-thiazole-5-carboxylate in Kushner et al., J. Org.     Chem. 1948, 13, 834ff; -   Methyl 2-amino-4-pyridinecarboxylate in Podany et al., J. Org. Chem.     1986, 51, 2988–2994; -   Methyl 5-amino-3-pyridinecarboxylate in Hawkins et al., J. Org.     Chem. 1949, 14, 328–332; -   Methyl 4-amino-2-pyrimidinecarboxylate in DE 2848912, -   Methyl 6-amino-4-pyrimidinecarboxylate in Zh. Org. Khim. 1981, 17,     312–317; -   Ethyl 5-amino-1,3-thiazole-2-carboxylate in Adams et al., J. Chem.     Soc. 1956, 1870–1873; -   Methyl 4-(aminomethyl)-2-thiophenecarboxylate in Peschke et al.,     Bioorg. Med. Chem. Lett. 1997, 7, 1969–1972; -   2-Amino-1,3-oxazole-4-carboxylic acid in Foulis et al., J. Med.     Chem. 1971, 14, 1075–1077; -   Methyl 4-aminopyridine-2-carboxylate in Mostier et al., J. Org.     Chem. 1955, 20, 283–285; -   Methyl 2-aminopyrimidine-3-carboxylate in Liebigs Ann. Chem. 1965,     209–211; -   5-Amino-1,3,4-thiadiazole-5-carboxylic acid in Liebigs Ann. Chem.     1963, 3; -   5-Amino-1,3,4-triazole-5-carboxylic acid in U.S. Pat. No. 3,023,210; -   4-Aminopyrrole-2-carboxylic acid in J. Med. Chem. 1983, 26, 1042; -   1-Methyl-3-aminopyrazole-5-carboxylic acid in Acta Chem. Scand.     1990, 44, 74; -   1-Methyl-5-aminopyrazole-3-carboxylic acid in Lee et al., J. Org.     Chem. 1989, 54, 428.

Conversion of compounds of the general formula XI and XII HNR_(E) ³—(CR_(E) ⁴R_(E) ⁵)_(f)—(QE)_(k)—(CR_(E) ⁶R_(E) ⁷)_(g)—W_(E)  (XI) NC—(CR_(E) ⁴R_(E) ⁵)_(f-l)—(QE)_(k)—(CR_(E) ⁶R_(E) ⁷)_(g)—W_(E)  (XII) into compounds of the general formula: A—NR_(E) ³—(CR_(E) ⁴R_(E) ⁵)_(f)—(QE)_(k)—(CR_(E) ⁶R_(E) ⁷)_(g)—W_(E)  (XIII) A—(CR_(E) ⁴R_(E) ⁵)_(f-l)—(QE)_(k)—(CR_(E) ⁶R_(E) ⁷)_(g)—W_(E)  (XIV), where W_(E) is COOSG₂ or NSG₃, can take place by methods known to the skilled worker and described, for example, in WO 97/08145. These building blocks can then be converted either directly—in the case of the corresponding free amines and carboxylic acids—or after elimination of the protective groups—into compounds of the general formula I (scheme 1).

However, it is also possible in principle for A to be introduced, as described in scheme 1, into compounds of type V, in which case the stated reaction conditions can be used, just as can variants not described here.

In schemes 3–7, a number of methods for introducing A are described by way of example, using in each case reaction conditions known and suitable for the particular reactions. It is moreover possible to make use of variants which are known per se but which are not mentioned here.

Ureas or thioureas (AE-1 to AE-3) can be prepared by conventional methods of organic chemistry, for example by reacting an isocyanate or an isothiocyanate with an amine, where appropriate in an inert solvent with heating (Houben-Weyl, Vol. VIII, 157 et seq.) (scheme 3).

Scheme 4 shows by way of example the preparation of compounds of type AE-4 as described, for example, by Blakemoore et al. in Eur. J. Med. Chem. 1987 (22) 2, 91–100, or by Misra et al. in Bioorg. Med. Chem. Lett. 1994, 4 (18), 2165–2170.

Unsubstituted or cyclic guanidine derivatives of the general formula AE-5 and AE-6 can be prepared using reagents which can be bought or obtained simply, as described, for example, in Synlett 1990, 745, J. Org. Chem. 1992, 57, 2497, Bioorg. Med. Chem. 1996, 6, 1185–1208; Bioorg. Med. Chem. 1998, 1185, or Synth. Comm. 1998, 28, 741–746.

Preparation of compounds of the general formula AE-7 can take place in analogy to U.S. Pat. No. 3,202,660, and compounds of the formula AE-9, AE-10, AE-11 and AE-12 in analogy to WO 97/08145. Compounds of the formula AE-8 can be prepared, as shown in Scheme 6, for example by the methods described by Perkins et al., Tetrahedron Lett. 1999, 40, 1103–1106. Scheme 6 summarizes the synthesis of said compounds:

Compounds of the general formula AE-13 can be prepared in analogy to Froeyen et al., Phosphorus Sulfur Silicon Relat. Elem. 1991, 63, 283–293, AE-14 in analogy to Yoneda et al., Heterocycles 1998, 15 N°-1, Spec. Issue, 341–344 (scheme 7). The preparation of corresponding compounds can also take place in analogy to WO 97/36859.

Compounds of the general formula AE-15 can be prepared as in Synthesis 1981, 963–965 or Synth. Comm. 1997, 27 (15), 2701–2707, AE-16 in analogy to J. Org. Chem. 1991, 56 (6), 2260–2262 (scheme 7).

The invention further relates to the use of the structural element of the formula I_(GL) —G—L  I_(GL) for preparing compounds which bind to integrin receptors.

The invention further relates to drugs comprising the structural element of the formula I_(GL).

The invention further relates to pharmaceutical preparations for oral and parenteral use containing at least one compound of the formula I in addition to conventional pharmaceutical excipients.

The compounds according to the invention can be administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional way. Administration can also take place with vapors or sprays through the nasopharyngeal space.

The dosage depends on the age, condition and weight of the patient and on the mode of administration. As a rule, the daily dose of active ingredient is between about 0.5 and 50 mg/kg of body weight on oral administration and between about 0.1 and 10 mg/kg of body weight on parenteral administration.

The novel compounds can be used in conventional solid or liquid pharmaceutical forms, for example as uncoated or (film-)coated tablets, capsules, powders, granules, suppositories, solutions, ointments, creams or sprays. These are produced in a conventional way. The active ingredients can for this purpose be processed with conventional pharmaceutical aids such as tablet binders, bulking agents, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, release-slowing agents, antioxidants and/or propellant gases (cf. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1991). The administration forms obtained in this way normally contain from 0.1 to 90% by weight of active ingredient.

The invention further relates to the use of the compounds of the formula I for producing drugs for the treatment of diseases. The compounds of the formula I can be used for treating human and animal diseases. The compounds of the formula I bind to integrin receptors. They are therefore suitable preferably as integrin receptor ligands and for producing drugs for treating diseases in which an integrin receptor is involved.

They can preferably be used to produce drugs for treating diseases in which, for example, there is excessive interaction between integrins and their natural ligands.

The compounds of the formula I preferentially bind to the α_(v)β₃ integrin receptor and can thus be used particularly preferably as ligands of the α_(v)β₃ integrin receptor and for treating diseases in which the α_(v)β₃ integrin receptor is involved.

They can preferably be used to produce drugs for treating diseases in which, for example, there is excessive interaction between the α_(v)β₃ integrin receptor and its natural ligands.

The compounds of the formula I are preferably used for influencing metabolic processes or regulatory mechanisms underlying particular diseases, such as, for example, inhibition of angiogenesis or for treating the following diseases:

cardiovascular diseases such as atherosclerosis, restenosis after vessel injury, and angioplasty (neointima formation, smooth muscle cell migration and proliferation),

acute kidney failure,

angiogenesis-associated microangiopathies such as, for example, diabetic retinopathy or rheumatoid arthritis,

blood platelet-mediated vascular occlusion, arterial thrombosis,

stroke, reperfusion damage after myocardial infarct or stroke,

cancers such as, for example, in tumor metastasis or tumor growth (tumor-induced angiogenesis),

osteoporosis (bone resorption after proliferation, chemotaxis and adhesion of osteoclasts to bone matrix),

high blood pressure, psoriasis, hyperparathyroidism, Paget's disease, malignant hypercalcemia, metastatic osteolytic lesions, inflammation, wound healing, cardiac insufficiency, CHF, and for

antiviral, antiparasitic or antibacterial therapy and prophylaxis (adhesion and internalization).

The following examples illustrate the invention but the selection of these examples is non-limiting.

I. SYNTHETIC EXAMPLES

I.A Precursors

Preparation of the Building Blocks

Methyl (E,Z)-[5-(2-tert-butoxy-2-oxoethyl)-6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene]acetate (1)

A solution of methyl (E,Z)-(6-oxo-5,6-dihydro-11H-dibenzo[b,e])-azepin-11-ylidene)acetate (27 g, 96.7 mmol) in 100 ml of DMF was added dropwise to a suspension of 4.7 g of NaH (60%; oil removed with n-pentane) in 400 ml of DMF at 0° C. and stirred for about min for complete formation of the anion. Then tert-butyl bromoacetate (18.9 g, 96.7 mmol) was added and the mixture was stirred at 0° C. for about 1.5 h. For workup, aqueous NH₄Cl solution was added to the mixture and, after concentration, the residue was taken up in CH₂Cl₂ and washed with saturated NaCl solution. Drying and concentration of the CH₂Cl₂ phase afforded 40.5 g of solid which was then stirred with pentane and dried at 30° C. in vacuo.

31.6 g; ESI-MS [M−tBu+H⁺]=338;

¹H-NMR (DMSO-d6, 200 MHz) E/Z mixture: δ (ppm) 7.65–7.1 (m, 8H), 6.3/6.25 (s, 1H), 4.5 (m, 2H), 3.6 (s, 3H), 1.35 (s, 9H).

Methyl [5-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5-H-dibenzo-[b,e]azepin-11-yl]acetate (2)

Methyl (E,Z)-[5-(2-tert-butoxy-2-oxoethyl)-6-oxo-5,6-dihydro-11-H-dibenzo[b,e]azepin-11-ylidene]acetate 1 (41 g, 104.2 mmol) was taken up in 1 l of 1:1 CH₃OH/ethyl acetate and, after addition of 3.1 g of catalyst (10% Pd on carbon), the mixture was hydrogenated at 50° C. under a pressure of 120 bar for 21 h. Filtration through Celite, washing with CH₃OH and evaporation of the combined phases afforded 41.1 g of the hydrogenation product as a white foam.

ESI-MS [M−tBu+H⁺]=340.05;

¹H-NMR (DMSO-d6, 270 MHz) diastereomer mixture: δ (ppm) 7.70–7.1 (m, 8H), 4.8–4.6 (m, 3H), 3.65/3.35 (s, 3H), 3.05 (m, 2H), 1.5/1.45 (s, 9H).

11-(2-Methoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]-azepin-5-yl acetate (3)

Methyl [5-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate 2 (30.5 g, 77.5 mmol) was taken up in 100 ml of CH₂Cl₂ and, at 0° C., 150 ml of TFA were added, and the mixture was stirred at 0° C. for about 1 h and then at RT. After the reaction was complete, the mixture was evaporated, and mixed with toluene 2× and again evaporated. 33.6 g of a yellowish oil were obtained as crude product; crystallization from acetone afforded 14.8 g of white solid.

ESI-MS [M+H⁺]=340;

¹H-NMR (DMSO-d6, 400 MHz) diastereomer mixture: δ (ppm) 7.7–7.05 (m, 8H), 4.85–4.6 (m, 2H), 4.45 (m, 1H), 3.6/3.45 (s, 3H), 3.3 (m, 1H), 3.1/3,05 (dd, 1H).

tert-Butyl (6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl) acetate (4)

-   a) Methyl     (E,Z)-(6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene)acetate     (62 g, 279.2 mmol) was hydrogenated in 1.8 1 of dioxane with 3.2 g     of Pd (10% on carbon) at 60° C. and 130 bar for 60 h. Filtration     through Celite and concentration of the filtrate afforded 62.3 g of     white solid, which was then stirred with n-pentane.

58.7 g; ESI-MS [M+H⁺]=282;

-   b) Methyl-(6-oxo-5,6-dihydro-1H-dibenzo[b,e]azepin-11-yl)-acetate     (25 g, 88.7 mmol) was dissolved in 145 ml of 4:1 dioxane/H₂O and,     after addition of 4.98 g of KOH, heated to reflux. A further 2.5 g     of KOH were added after 2 h. After the reaction was complete, the     reaction mixture was concentrated and, after addition of H₂O and     adjustment to pH 2 with 2N HCl, extracted 2× with CH₂Cl₂. The     combined organic phases were washed with saturated NaCl solution,     dried (MgSO₄) and concentrated. The crude product obtained in this     way was stirred with n-pentane and dried.

21.5 g, ESI-MS [M+H⁺]=268.05

-   c) (6-Oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetic acid (18.8     g; 70.34 mmol) was suspended in 80 ml of benzene and heated to     reflux. Over a period of 1 h, 5.3 eq. of dimethylformamide     di-tert-butyl acetal (75.9 g) were added dropwise. After the     reaction was complete, the mixture was evaporated, and the residue     was taken up in CH₂Cl₂, washed with NaHCO₃ and saturated NaCl     solution, dried and concentrated. The brown solid obtained in this     way was purified by stirring with methyl tert-butyl ether.

26.9 g; ESI-MS [M−tBu+H+]=268.05;

¹H-NMR (270 MHz, DMSO-d6): d (ppm) 10.55 (s, 1H), 7.8–7.0 (m, 8H), 4.35 (m, 1H), 2.75 (d, 2H), 1.2 (s, 9H).

Ethyl 3-[11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl]propanoate (5)

tert-Butyl (6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate 4 (2 g, 6.18 mmol) was dissolved in 25 ml of dry DMF and, at 10° C., 2.1 eq. of KOtBu (1.5 g) were added, and the mixture was stirred for about 20 min. Then, at RT 2.5 g of ethyl bromopropionate were added dropwise and, after stirring at RT for 1 h, further KOtBu (0.2 g) and ethyl bromopropionate (0.8 g) were added. After a further 2 h, the mixture was diluted with CH₂Cl₂, washed with H₂O, dried and concentrated. Chromatography on silica gel (CH₂Cl₂CH₃OH 1 to 25%) afforded 1.2 g of the required product and 2.0 g of nonreacted precursor.

ESI-MS [M+H+]=424.15

3-[11-(2-tert-Butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl]propanoic acid (6)

Ethyl 3-[11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5-H-dibenzo[b,e]azepin-5-yl]propanoate 5 (2.55 g, 6.02 mmol) was dissolved in 15 ml of 2:1 dioxane/H₂O and, after addition of 0.17 g of LiOH, stirred at RT. After the reaction was complete, the mixture was acidified with 2N HCl and, after addition of CH₂Cl₂, washed with saturated NaCl solution, dried and concentrated.

2.35 g; ESI-MS [M−tBu+H+]=340.15;

¹H-NMR (DMSO-d6, 200 MHz) diastereomer mixture: d (ppm) 7.75–7.05 (m, 8H), 4.8–3.8 (m, 3H), 3.5–3.1 (m, overlapped by H₂O), 2.75 (m, 2H, 1.3/1.2 (s, 9H).

tert-Butyl [6-(4,5-dihydro-1H-imidazol-2-yl)-3-pyridinyl]methyl-carbamate (trifluoroacetate) (7)

-   a) tert-butyl (6-cyanopyridin-3-yl)methylcarbamate (5.0 g, 21.43     mmol) in 300 ml of CH₃OH were mixed with 3.55 g of sodium     methanolate. After 1 h at RT, 2.6 g of ethylenediamine     (hydrochloride) were added and stirred overnight. The reaction     mixture was evaporated and the resulting residue was stirred with a     mixture of 100 ml of CH₂Cl₂ and 1 ml of CH₃OH. Insoluble solids were     filtered off with suction, the filtrate was concentrated, and the     residue was taken up in H₂O and again washed with CH₂Cl₂.     Evaporation of the aqueous phase afforded 5.3 g of a white solid;     ESI-MS [M+H⁺]=277.25. -   b) 0.9 g of the Boc-protected amine in 20 ml of CH₂Cl₂ were mixed     with 10 ml of TFA and stirred at 0° C. for 2 h. Evaporation of the     reaction mixture afforded 1.75 g of a yellowish oil which was     immediately employed further.     -   The amine required for further reaction was obtained by         eliminating the Boc group with TFA (under standard conditions);         the isolated TFA salts were then employed directly in the         appropriate couplings.

tert-Butyl 1H-benzimidazol-2-ylmethylcarbamate (8)

3.32 g of a 30% NaOCH₃ solution were added to tert-butyl cyanomethylcarbamate (3 g; 19.21 mmol) in 20 ml of CH₃OH, and the mixture was stirred at room temperature for 1 h. After addition of 3.4 g of 1,2-phenylenediamine bishydrochloride, the reaction mixture was stirred further overnight and then added to 100 ml of H₂O, and the resulting solid was filtered off and dried in vacuo.

3.45 g; ESI-MS [M+H+]=248.15;

¹H-NMR (270 MHz; DMSO-d6) d (ppm) 12.60 (s, 1H), 7.30–7.15 (m 3H), 7.05 (m 2H), 4.15 (d, 2H), 1.29 (s, 9H).

The amine required for further reaction was obtained by eliminating the Boc group with TFA (under standard conditions); the isolated TFA salts were then employed directly in the appropriate couplings.

tert-Butyl 3H-imidazo[4,5-b]pyridin-2-ylmethylcarbamate (9)

A mixture of tert-butyl cyanomethylcarbamate (1.61 g; 10 mmol), 2,3-diaminopyridine (0.56 g; 5 mmol), N-acetylcysteine (1.68 g; 10 mmol) in 10 ml of CH₃OH was heated at 50° C. for 89 h. It was then concentrated, and the residue was taken up in a little CH₃OH and filtered through an acidic ion exchanger (acetate on polymeric support). Renewed concentration and chromatography on silica gel (CH₂Cl₂/CH₃OH 5%) afforded 1.09 g of the required product;

ESI-MS [M+H⁺]=249.15

¹H-NMR (270 MHz; DMSO-d6) d (ppm) 8.30 (m, 1H), 7.90 (m, 1H), 7.45 (m, broad, 1H), 7.20 (m 1H), 4.40 (d, 2H), 1.0 (s, 9H).

The amine required for further reaction was obtained by eliminating the Boc group with TFA (under standard conditions); the isolated TFA salts were then employed directly in the appropriate couplings.

[1-(2-Pyridinyl)-4-piperidinyl]methanamine (10)

-   a) 1-tert-Butyloxycarbonyl-4-(aminomethyl)piperidine (14 g; 65.33     mmol; prepared as described by Prugh et al., Synthetic     Communications 22 (16), 2361–2365 (1992)) was dissolved in 50 ml of     THF and, at 5° C., N-methylmorpholine (6.6 g) and benzyl     chloroformate (12.6 g) were added, and the mixture was stirred for     about 2 h. It was then concentrated, and the residue was taken up in     CH₂Cl₂, washed with saturated NaCl solution, dried and filtered. The     residue after concentration was 23.5 g of a yellow oil which was     crystallized from methyl tert-butyl ether.

18 g; ESI-MS [M+H+]=293.15

-   b) 25 ml of TFA were added to     -   1-tert-butyloxycarbonyl-4-({[benzyloxy)carbonyl]amino}-methyl)piperidine         10a (15 g; 43.05 mmol) in 125 ml of CH₂Cl₂ at 0° C., and the         mixture was stirred at 10° C. for 20 min and then at RT.         Concentration of the mixture and crystallization of the         resulting residue from diethyl ether afforded 14.5 g of the free         amine as TFA salt (ESI-MS [M+H⁺]=249.25; melting point: 109–110°         C.).     -   5 g of the TFA salt and 2.79 g of ethyldiisopropylamine (DIPEA)         in 15 ml of 2-fluoropyridine were heated to reflux. After the         reaction was complete, the mixture was concentrated, and the         residue was taken up in ethyl acetate and washed 4× with H₂O and         saturated NaCl solution. Drying, filtration and concentration         afforded 4.49 g of a pale brown oil, which was crystallized from         n-pentane.

4.02 g; ESI-MS [M+H⁺]=362.15

-   c) 3.9 g of (10b) in 150 ml of CH₃OH were hydrogenated with 0.2 g of     Pd (10% on carbon) under standard conditions. Filtration of the     reaction mixture through Celite and concentration afforded 2.3 g;

ESI-MS [M+H+]=192.15;

¹H-NMR (270 MHz; DMSO-d6) d (ppm) 8.1 (m, 1H), 7.5 (m, 1H), 6.8 (m, 1H), 6.55 (m, 1H), 4.3 (m, 2H), 2.7 (m 2H), 2.45 (m, 2H), 1.75 (m 2H), 1.5 (m 1H), 1.05 (m 2H).

1-tert-Butyloxycarbonyl-4-[(2-pyridinylamino)methyl]piperidine (11)

1-tert-Butyloxycarbonyl-4-(aminomethyl)piperidine (3 g; 14 mmol) and 10 ml of 2-fluoropyridine were heated to reflux for 4 h. Concentration and stirring of the crude product in n-pentane afforded 3 g of a white solid, melting point: 126–130° C.;

ESI-MS [M+H+]=292.15.

The amine required for further reaction was obtained by eliminating the Boc group with TFA (under standard conditions); the isolated TFA salts were then employed directly in the appropriate couplings.

N-[4-(Aminomethyl)benzyl]-2-pyridinamine (12)

-   a) 20 g of 2-aminopyridine were dissolved in 100 ml of CH₃OH and,     after adjustment to pH 6 with isopropanolic HCl, 36 g of     p-cyanobenzaldehyde were added. 9.35 g of sodium cyanoborohydride     were added in portions over the course of 1 h and the mixture was     stirred overnight. For workup, the suspension was concentrated, and     the residue was taken up in 100 ml of water and adjusted to pH >10     with KOH. The aqueous phase was saturated with NaCl and extracted 3×     with diethyl ether. The ether phase was filtered to remove a     precipitate and then washed 3× with FeSO₄ solution, dried and     concentrated. Purification of the residue by chromatography on     silica gel (heptane/ethyl acetate 1:1) afforded 28.15 g of     4-[(2-pyridinylamino)methyl]benzonitrile. -   b) 10 g of 4-[(2-pyridinylamino)methyl]benzonitrile were dissolved     in 280 ml of ammoniacal methanol and, after addition of 10 g of     Raney nickel, hydrogenated for 24 h. The residue after filtration     and concentration was chromatographed on silica gel (ethyl     acetate/ethanol 1:3).

5.18 g, ESI-MS: [M+H+]=214.

tert-Butyl [4-(1H-benzimidazol-2-yl)-1,3-thiazol-2-yl]methyl-carbamate (13)

In analogy to the preparation of 8, 1.89 g of a 30% NaOCH₃ solution were added to tert-butyl (4-cyano-1,3-thiazol-2-yl)methylcarbamate (2.5 g; 10.45 mmol) in 25 ml of CH₃OH, and the mixture was stirred at room temperature for 2 h. Addition of 1.9 g of 1,2-phenylenediamine bishydrochloride was followed by stirring overnight, and then the reaction mixture was added to 100 ml of H₂O, and the solid resulting after filtration was dried in vacuo.

3.0 g; ESI-MS: [M+H+]=331.15,

¹H-NMR (400 MHz; DMSO-d6) d (ppm) 8.25 (s, 1H), 7.95 (m, 1H), 7.65 (m, 1H), 7.55 (m, 1H), 7.2 (m, 2H), 4.55 (m, 2H), 1.45 (s, 9H).

The amine required for further reaction was obtained by eliminating the Boc group with TFA (under standard conditions); the isolated TFA salts were then employed directly in the appropriate couplings.

Di(tert-butyl) 4-(1H-benzimidazol-2-yl)benzylimidodicarbonate (14)

Di(tert-butyl) 4-cyanobenzylimidodicarbonate (10 g; 30.1 mmol) was dissolved in 200 ml of pyridine and, after addition of 45 ml of triethylamine, H₂S was passed in at 0° C. for 1.5 h and the mixture was kept at RT overnight. The reaction mixture was concentrated in vacuo and coevaporated with toluene twice. Stirring of the resulting residue in diethyl ether afforded 8.5 g of white solid.

The thioamide (6 g; 16.37 mmol) was suspended in 40 ml of CH₂Cl₂ and, after addition of 22.3 g of CH₃I, stirred at RT overnight. The mixture was then evaporated, taken up in 20 ml of CH₃OH and, after addition of 1,2-phenylenediamine (1.95 g; 18.01 mmol), again stirred at RT overnight. Concentration of the mixture afforded 6.9 g of yellow solid.

ESI-MS [M+H+]=424.25;

The amine required for further reaction was obtained by eliminating the Boc group with TFA (under standard conditions); the isolated TFA salts were then employed directly in the appropriate couplings.

[5-(2-Methoxy-2-oxoethyl)-11-oxo-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl]acetic acid (37)

-   a) A mixture of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one     (10 g; 47.6 mmol; preparation as described in Pharmazie 45, 1990,     555–559), 100 g of methyl bromoacetate, 0.5 g of KI and 180 ml of     DMF was heated at 60° C. for 110 h. Concentration of the mixture,     chromatography of the crude product on silica gel (CH₂Cl₂/CH₃OH     3→5%) and crystallization of the resulting oil from ethyl acetate     afforded 7.1 g of gray solid; ESI-MS [M+H⁺]=283

¹H-NMR (400 MHz; DMSO-d₆): δ (ppm) 10.3 (s, 1H), 7.65 (d, 2H), 7.45 (m, 2H), 7.05–7.2 (m, 4H), 4.75 (d, 2H), 3.6 (s, 3H).

-   b) A solution of methyl     (11-oxo-10,11-dihydro-5H-dibenzo[b,e]-[1,4]diazepin-5-yl)acetate 37a     (7 g; 24.8 mmol) in 40 ml of DMF was added dropwise to a suspension     of 1.3 g of NaH (60%; oil removed with n-pentane) in 10 ml of DMF at     5° C., and the mixture was stirred for about 30 min to complete     formation of the anion. Then tert-butyl bromoacetate (5.4 g, 27.7     mmol) was added dry and the mixture was stirred at 10° C. for about     2 h. For workup, the mixture was mixed with H₂O, diluted with CH₂Cl₂     and washed with saturated NaCl solution. Drying and concentration of     the CH₂Cl₂ phase afforded a black oil, which was purified by     chromatography on silica gel (CH₂Cl₂/CH₃OH 2→10%);

7.8 g; ESI-MS [M−tBu+H⁺]=341

-   c) tert-Butyl     [5-(2-methoxy-2-oxoethyl)-11-oxo-5,11-dihydro-10H-dibenzo[b,e][1,4]diazepin-10-yl]acetate     37b (7.8 g; 19.67 mmol) in 15 ml of CH₂Cl₂ was mixed with 10 ml of     TFA and stirred at RT for 2 h. Concentration of the mixture and     drying afforded 7.4 g of brown solid; ESI-MS [M+H⁺]=341

N-[4-(Aminomethyl)-1,3-thiazol-2-yl]-N′-benzylurea (hydrochloride) (38)

-   a) A solution of 123 g of pyridinium bromide perbromide in 600 ml of     THF was slowly added dropwise to 2-(2-oxopropyl)-1H-isoindole-1,3     (2H)-dione (70 g; 0.345 mol) in 600 ml of THF, and the mixture was     then stirred for about 3 h. For workup, the precipitated solids were     filtered off, and the mother liquor was concentrated, taken up in     ethyl acetate and thoroughly washed with aqueous bisulfite solution.     Drying and concentration afforded 150 g of a yellow oil, which was     stirred with methyl tert-butyl ether.

63.4 g; m.p.: 142 to 143° C.; ESI-MS [M+H⁺]=283.95

-   -   b) 2-(3-Bromo-2-oxopropyl)-1H-isoindole-1,3 (2H)-dione 38a (6 g;         21.27 mmol) and thiourea (2 g; 26.27 mmol) were stirred in 70 ml         of THF at RT for about 2 h. The resulting precipitate was         filtered off with suction and dried.

5 g; ESI-MS [M+H⁺]=260.05

-   c) 2-[(2-Amino-1,3-thiazol-4-yl)methyl]-1H-isoindole-1,3 (2H)-dione     hydrobromide 38b (4.5 g; 13.23 mmol), benzyl isocyanate (1.8 g,     13.52 mmol) and 1.7 g of DIPEA were heated to reflux in 50 ml of     toluene. After the reaction was complete, the mixture was     evaporated, and the residue was taken up in CH₂Cl₂ and washed with 1     N HCl, saturated NaHCO₃ and NaCl solutions. Drying and concentration     afforded 4.7 g of orange solid, which was recrystallized from CH₃OH.

3.0 g; ESI-MS [M+H⁺]=393.05

¹H-NMR (360 MHz, DMSO) δ ppm: 10.65 (s, 1H), 7.9 (m, 4H), 7.25 (m, 5H), 6.85 (s, 1H), 4.7 (s, 2H), 4.35 (d, 2H),

-   d)     N-Benzyl-N′-{4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-methyl]-1,3-thiazol-2-yl}urea     38c (3 g; 7.64 mmol) was suspended in 50 ml of CH₃OH and, after     addition of 2 g of hydrazine hydrate, stirred at RT for 2 h. The     resulting solids were filtered off, and the resulting mother liquor     was evaporated and stirred with 0.5 N HCl. Renewed filtration and     evaporation of the mother liquor led to a concentration of the     required product, and thus this purification step was repeated 3×.

0.78 g; ESI-MS [M+H⁺]=263.05

[4-(Aminomethyl)-1,3-thiazol-2-yl]guanidine (bishydrochloride) (39)

-   a) 2-(3-Bromo-2-oxopropyl)-1H-isoindole-1,3 (2H)-dione 38a (10 g;     35.45 mmol) and 2-iminothiobiuret (4.6 g; 38.99 mmol) were stirred     in 150 ml of THF at RT for about 2 d. The resulting precipitate was     filtered off with suction and dried; 11.4 g;

ESI-MS [M+H⁺]=302.15.

-   b) 5 g of 39a were treated with hydrazine hydrate in CH₃OH in     analogy to 38d. Stirring of the resulting crude product with 0.5 N     HCl and subsequently with ethanol afforded 3.16 g;

ESI-MS [M+H⁺]=172.05.

N-[4-(Aminomethyl)benzyl]-N′-benzylurea (40)

340 mg (2.5 mmol) of diamino-p-xylene were introduced into 15 ml of acetonitrile and cooled to 0 to 5° C. and, over the course of 5 min, 0.29 ml of benzyl isocyanate was added and the mixture was then stirred at RT for 16 h. The resulting suspension was added to water, and the precipitate was filtered off with suction, washed with water and dried (402 mg). ESI-MS [M+H⁺]=270.

N-[3-(Aminomethyl)phenyl]-N′-benzylurea (hydrochloride) (41)

-   a) 4.7 g (25 mmol) of m-nitrobenzylamine were added to 250 ml of     CH₂Cl₂ and, after addition of 1.36 ml of DIPEA, the mixture was     refluxed until the benzylamine had dissolved. The solution was     cooled to 0° C., and di-tert-butyl carbonate (1.1 eq.) was added     dropwise. The mixture was then stirred at RT for 16 h, and     subsequently the solution was extracted with water and saturated     NaHCO₃ solution. The organic phase was dried and concentrated, and     the resulting residue was crystallized from 30 ml of diethyl ether     (5.07 g). -   b) 4.69 g of the above nitro compound were dissolved in 50 ml of     ethanol and hydrogenated with 460 mg of 5% Pd on active carbon under     atmospheric pressure. The reaction was complete after 2 h. The     filtrate after filtration was concentrated, and the remaining oil     was immediately reacted further (3.80 g). -   c) The oil was dissolved in 100 ml of THF, and 3.66 ml of DIPEA and     then dropwise 2.60 g of benzyl isocyanate were added to the     solution. The mixture was stirred at RT for 16 h, then under reflux     for 6 h and then at RT for a further 16 h. It was concentrated and     crystallized from 30 ml of ethyl acetate, and the resulting     precipitate was filtered off with suction and dried; 4.90 g; ESI-MS     [carbamic acid fragment+H⁺]=300. -   d) The Boc compound was dissolved in 20 ml of THF, and 5 ml of HCl     in diethyl ether (saturated at 0° C.) were added. After 1 h, a     further 15 ml of HCl in diethyl ether were added and the mixture was     stirred for 16 h. The precipitate which had formed was filtered off     with suction, washed with THF and diethyl ether and dried (3.72 g).     ESI-MS [M+H⁺]=256.

3-Amino-N-(1H-imidazol-2-yl)propanamide (42)

-   a) Z-β-alanine (10 g; 44.8 mmol) was dissolved in 200 ml of DMF, and     15.86 g (3.5 eq) of N-methylmorpholine and 5.9 g (0.5 eq) of     2-aminoimidazole sulfate were added. At −10° C., 7.87 g (1.3 eq) of     HOBt and 11.16 g (1.3 eq) of     N′-(dimethylaminopropyl)-N-ethylcarbodiimide were added, and the     mixture was stirred for 1 h while warming to RT and then for 18 h.     150 ml of diethyl ether were added, whereupon a white solid     precipitated and was filtered off with suction. The residue was     washed with cold diethyl ether and suspended in ethyl acetate, and 1     N HCl was added until the reaction was acidic. The aqueous solution     was extracted 1× with ethyl acetate, and then the aqueous phase was     adjusted to a basic pH with 10% NaOH at 4° C. The resulting     precipitate was filtered off with suction and washed with water. 5.4     g; ESI-MS [M+H⁺]=289.05.) -   b) 5.3 g of the Z compound 42a were suspended in 250 ml of ethanol,     and 530 mg of 10% Pd on active carbon were added. The mixture was     hydrogenated with H₂ at RT for 18 h and then diluted with CH₃OH, and     the suspension was boiled to dissolve the product precipitate.     Filtration and concentration of the solution afforded 1.5 g; ESI-MS     [M+H⁺]=155.05.

4-(Aminomethyl)-N-benzylpiperidine-1-carboxamide (43)

-   a) Benzyl 4-(aminomethyl)-1-piperidinecarboxylate (trifluoroacetate)     (4 g; 11.04 mmol; preparation as described in 10b) was suspended in     60 ml of toluene and heated with 1.43 g of DIPEA and benzyl     isocyanate (1.62 g, 12.14 mmol) to reflux for 4 h. After evaporation     of the reaction mixture, the residue was taken up in CH₂Cl₂ and     extracted 2× each with 1 N HCl and saturated NaCl solutions, and the     organic phase was dried and concentrated.

4.2 g; ESI-MS [M+H⁺]=382.25.

-   b) 4 g of benzylurea 43a were dissolved in a 3:1 ethyl acetate/CH₃OH     mixture with heating and, after addition of 0.2 g of 10% Pd on     active carbon, hydrogenated under standard conditions at 35 to     40° C. After the reaction was complete, the mixture was filtered     through Celite and evaporated.

2.8 g; ESI-MS [M+H⁺]=248.15.

¹H-NMR (400 MHz, DMSO) δ ppm: 7.4–7.15 (m, 11H), 7.05 (t, 1H), 5.08 (s, 2H), 4.25 (d, 2H), 3.95 (d, 2H), 2.8 and 2.65 (each m, 2H), 1.6 (m, 3H), 0.95 (m, 2H).

[4-(1H-Benzimidazol-2-yl)-thien-2-yl]methanamine (trifluoroacetate) (44)

The tert-butyl-(4-cyanothien-2-yl)methylcarbamate used as precursor was prepared by standard methods from 5-(aminomethyl)-3-thiophenecarbonitrile (WO 98/06741).

-   a) 3.6 g of a 30% NaOCH₃ solution were added to tert-butyl     (4-cyanothien-2-yl)methylcarbamate (5 g; 20.98 mmol) in 70 ml of     CH₃OH and the mixture was stirred at room temperature for 2 h.     Addition of 3.6 g of 1,2-phenylenediamine bishydrochloride was     followed by stirring overnight, and then the reaction mixture was     added to 50 ml of H₂O and extracted with CH₂Cl₂. Drying and     concentration of the organic phase afforded 4.3 g of a yellow solid,     which was purified by chromatography on silica gel (CH₂Cl₂/CH₃OH     1→10%).

1.6 g; ESI-MS: [M+H⁺]=333.15.

-   b) 1.5 g of the Boc compound 44a were dissolved in 10 ml of CH₂Cl₂     and, after addition of 15 ml of TFA at 0° C., stirred at room     temperature for 2 h. Evaporation of the reaction mixture and     stirring with n-pentane afforded 1.5 g of the amine as     trifluoroacetate.

[5-(1H-Benzimidazol-2-yl)thien-2-yl]methanamine (45)

Preparation took place in analogy to 44 starting from 5-(aminomethyl)thiophene-2-carbonitrile (preparation as described in WO 95/23609). The crude product obtained after TFA cleavage was dissolved in water and extracted 2× with diethyl ether, and the aqueous phase was adjusted to pH 10–11 and then extracted 2× with ethyl acetate. The aqueous phase was saturated with NaCl and again extracted with ethyl acetate. The combined organic phases were dried and concentrated (6.3 g); ESI-MS [M+H⁺]=230.1.

2-(Piperidin-4-ylamino)pyridine (46)

-   a) Ethyl 4-amino-1-piperidinecarboxylat (6 g, 34.8 mmol) and 25 g of     2-fluoropyridine were refluxed for 48 h. The solid formed after     cooling was filtered off with suction, stirred with n-pentane and     dried; 6.26 g of yellow powder;

ESI-MS [M+H⁺]=250.15.

-   b) 6 g of ethyl 4-(pyridin-2-ylamino)piperidine-1-carboxylate 46a     were refluxed in 30 ml of 47% HBr for 6 h. Evaporation of the     mixture, stirring of the resulting crude product with ethyl     acetate/CH₃OH (9:1) and renewed drying afforded 7.1 g of white     solid; ESI-MS [M+H⁺]=178.15.

N-[4-(Aminomethyl)phenyl]-1H-benzimidazole-2-amine (hydrochloride) (47)

-   a) 20 g of tert-butyl 4-aminobenzylcarbamate (89.97 mmol)—dissolved     in 100 ml of CH₃CN—were added dropwise to a solution of 24.5 g of     thiocarbonyldiimidazole and 1.56 g of imidazole in 600 ml of CH₃CN     at 0° C., and the mixture was stirred at RT overnight. Then 19.5 g     of 1,2-phenylenediamine were added and the mixture was again stirred     at RT for 2 h. For work up, the reaction mixture was evaporated in     vacuo, and the residue was taken up in CH₂Cl₂, washed 7× with 10%     citric acid solution and 2× with saturated NaCl solution, dried over     Na₂SO₄, filtered and concentrated. The crude product obtained in     this way (31.78 g; brown foam) was immediately reacted without     further purification; ESI-MS [M+H⁺]=373.15.

¹H-NMR (360 MHz, DMSO) δ ppm: 9.5 and 9.05 (each s, 1H), 7.45 (d, 2H), 7.35 (m, 1H), 7.20 (d, 1H), 7.15, 6.95, 6.75, 6.60 (each m, 1H), 4.85 (s, 2H), 4.10 (d, 2H), 1.35 (s, 9H).

-   b) The crude product 47a was dissolved together with 36.7 g of HgO     (yellow) and 0.4 g of sulfur in 750 ml of ethanol and refluxed for     2 h. The reaction mixture was then filtered twice through Celite and     evaporated to dryness; 20.7 g,

ESI-MS [M+H⁺]=339.15.

-   c) 7 g of the crude product 47b were introduced into 70 ml of CH₂Cl₂     and, after addition of 35 ml of HCl in diethyl ether (saturated at     0° C.), stirred at RT for 2 h. The resulting precipitate was     filtered off with suction, washed with CH₂Cl₂ and dried.

6.7 g of brown amorphous solid; ESI-MS [M+H⁺]=239.15

¹H-NMR (360 MHz, DMSO) δ ppm: 11.6 (s broad, 1H), 8.4 (s broad, 3H), 8.25 (s broad, 1H), 7.65 and 7.55 (each d, 2H), 7.45 and 7.3 (each m, 2H), 4.19 (m, 2H).

N¹-(1H-Benzimidazol-2-yl)pentane-1,5-diamine (hydrochloride) (48)

Preparation took place in analogy to the synthesis of 47 starting from 7 g of N-Boc-1,5-diaminopentane hydrochloride (29.3 mmol). After reaction in analogy to 47a, 10.3 g of N-Boc-5-{[(2-aminoanilino)carbothioyl]amino}pentan-1-amine were obtained; ESI-MS [M+H⁺]=353.25. Cyclodesulfurization and subsequent elimination of the Boc group with TFA afforded an oily crude product, which was taken up in CH₃OH and converted into the corresponding hydrochloride with 250 ml of ethereal HCl (saturated at 0° C.). Stirring of the resulting solids with a CH₃OH/methyl tert-butyl ether mixture afforded 1.8 g of a reddish amorphous solid.

¹H-NMR (360 MHz, DMSO) δ ppm: 9.30 (t, 1H), 8.15 (s broad, 3H), 7.40 and 7.25 (each m, 2H), 3.35 (m, 2H overlapped by H₂O peak), 2.80 (m, 2H), 1.65 (m, 4H), 1.45 (m, 2H).

N¹—(1H-Benzimidazol-2-yl)butane-1,4-diamine (trifluoroacetate) (49)

Preparation took place in analogy to the preparation of compound 47 starting from 9.87 g of N-Boc-1,4-diaminobutane (52.3 mmol). After reaction in analogy to 49a, 17.08 g of N-Boc-4-{[(2-aminoanilino)carbothioyl]amino}butan-1-amine were obtained; ESI-MS [M+H⁺]=338.99.

Subsequent cyclodesulfurization and Boc elimination with TFA afforded a brown solid, which was stirred several times with n-pentane and then recrystallized from a CH₃OH/methyl tert-butyl ether mixture; 14.35 g, ESI-MS [M+H⁺]=205.15.

¹H-NMR (360 MHz, DMSO) δ ppm: 9.20 (t, 1H), 7.80 (s broad, 3H), 7.35 and 7.20 (each m, 2H), 3.40 (m, 2H partially overlapped by H₂O peak), 2.80 (m, 2H), 1.65 (m, 4H).

N-(Piperidin-4-ylmethyl)-1H-benzimidazol-2-amine (trifluoro-acetate) (50)

-   a) A solution of tert-butyloxycarbonyl-4-(aminomethyl)-1-piperidine     (5.39 g; 25 mmol) in 25 ml of CH₃CN was added dropwise to 6.75 g of     thiocarbonyldiimidazole and 0.5 g of imidazole in 100 ml of CH₃CN at     0° C., and the mixture was stirred at RT for 3 h. Then     1,2-phenylenediamine (5.5 g; 50.86 mmol) was added and the mixture     was heated at 60° C. for about 1 h. The solid resulting on cooling     was filtered off with suction and dried.

6.79 g; ESI-MS [M+H⁺−^(t)Bu]=309.15.

-   b)     tert-Butoxycarbonyl-4-({[(2-aminoanilino)carbothioyl]-amino}methyl)1-piperidine     50a (5 g; 13.72 mmol), 5.94 g of HgO (yellow) and 0.6 g of sulfur in     150 ml of ethanol were refluxed for 1 h. The mixture was filtered 2×     through Celite and evaporated, and the resulting crude product was     purified by chromatography on silica gel (CH₂Cl₂/CH₃OH 5→25%).

2.65 g; ESI-MS [M+H⁺]=331.25.

¹H-NMR (360 MHz, DMSO) δ ppm: 7.15 and 6.9 (each m, 2H), 3.95 (d, 2H), 3.2 (m 2H), 2.7 (br m; 2H), 1.8 (m, 1H), 1.7 (m, 2H), 1.35 (s, 9H), 1.05 (m, 2H).

-   c)     tert-Butyloxycarbonyl-4-[(1H-benzimidazol-2-ylamino)methyl]-1-piperidine     50b (2.65 g; 8.02 mmol) were treated with 10 ml of TFA under     standard conditions. Concentration and stirring of the crude product     with n-pentane afforded 2.3 g; ESI-MS [M+H⁺]=231.15.

¹H-NMR (360 MHz, DMSO) δ ppm: 13.25 (s, 1H), 9.35 (m, 1H), 8.8 and 8.5 (each br s, 1H), 7.4 and 7.20 (each m, 2H), 3.3 (m, 4H), 2.85 (m, 2H), 1.9 (m, 3H), 1.35 (m, 2H).

N-[4-(Aminomethyl)-1,3-thiazol-2-yl]pyridin-2-amine (bishydrochloride) (51)

-   a) 2-Aminopyridine (11 g; 116.9 mmol) and benzyl isothiocyanate (21     g; 128.7 mmol) were refluxed in 250 ml of acetone for 3 h. The     mixture was then evaporated and the resulting residue was stirred     first with acetone/n-pentane and then only with n-pentane.

21.4 g; ESI-MS [M+H⁺]=258.05.

-   b) N-Benzoyl-N′-pyridin-2-ylthiourea 51a (5 g; 19.43 mmol) was     introduced into 100 ml of an acetone/CH₃OH mixture. 1.34 g of K₂CO₃     in 5 ml of H₂O were added and the mixture was refluxed for 2 h. For     workup, the precipitate which had formed was filtered off, the     mother liquor was evaporated, and the resulting residue was added to     H₂O. Extraction with CH₂Cl₂, drying and evaporation of the organic     phases afforded 5.4 g;

ESI-MS [M+H⁺]=154.05.

¹H-NMR (270 MHz, DMSO-d₆) δ ppm: 10.65 (s, 1H), 10.55 (s, 1H), 8.9 (s, 1H), 8.25, 7.75, 7.20, 7.10 (each m, 1H).

-   c) N-Pyridin-2-ylthiourea 51b (5 g; 35.9 mmol) and     2-(3-bromo-2-oxopropyl)-1H-isoindole-1,3 (2H)-dione (9.1 g; 32.26     mmol) were stirred in 500 ml of THF at RT for 2 h. The precipitate     which had formed was filtered off and dried. 12.3 g of white solid;     ESI-MS [M+H⁺]=337.05. -   d) Elimination of the phthaloyl group was carried out analogously     starting from     2-{[2-(pyridin-2-ylamino)-1,3-thiazol-4-yl]methyl}-1H-isoindole-1,3(2H)-dione     51c (10 g; 23.96 mmol) with 7 g of hydrazine hydrate in 250 ml of     CH₃OH. Subsequent workup afforded 4.15 g of yellow solids; ESI-MS     [M+H⁺]=207.05.

N-[5-(Aminomethyl)-1,3-thiazol-2-yl]pyridin-2-amine (bishydrochloride) (52)

Preparation took place in analogy to 51 using 2-chloro-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanal (preparation described in THL 39 (1998), 8085–8088). After cleavage of the phthaloyl group with hydrazine hydrate under standard conditions and stirring the crude product with CH₂Cl₂, 1.12 g of yellow solids were obtained; ESI-MS [M+H⁺]=207.05.

N-[5-(Aminomethyl)-1,3-thiazol-2-yl]guanidine (dihydrochloride) (53)

-   a) 31 g (130 mmol) of     2-chloro-3-(1,3-dioxo-1,3-dihydro-2H-iso-indol-2-yl)propanal     (preparation described in THL 39 (1998), 8085–8088) and 15.4 g of     amidinothiourea were heated in 200 ml of n-butanol at 110° C. for     75′, and then the mixture was evaporated and the residue was mixed     with CH₂Cl₂ and concentrated NH₃. Evaporation of the organic phase,     purification of the residue by chromatography on silica gel     ((CH₂Cl₂/CH₃OH 0 to 5%) and crystallization from acetone afforded     12.3 g of     N-{5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazol-2-yl}guanidine. -   b) 1 g of 53a in 20 ml of CH₃OH was mixed with 0.81 ml of hydrazine     hydrate and stirred at RT for 2 h. The mixture was then cooled to     0° C. and filtered, and the filtrate was concentrated and stirred     with dilute HCl. This procedure was repeated several times, and the     crude product obtained in this way was then stirred with ethanol;     0.92 g of white solids, ESI-MS [M+H⁺]=172.05.

tert-Butyl 2-[4-(1H-benzimidazol-2-yl)phenyl]ethylcarbamate (54)

Preparation took place in analogy to the synthesis of building block 14 starting from tert-butyl 2-(4-cyanophenyl)ethylcarbamate. The crude product obtained after reaction with H₂S, alkylation with CH₃I and reaction with 1,2-phenylenediamine was purified by chromatography on silica gel (CH₂Cl₂/CH₃OH 4 to 50%) (4.8 g); ESI-MS [M+H⁺]=338.15.

→ the amine required for the subsequent reaction was obtained by eliminating the Boc group with TFA (under standard conditions); the isolated TFA salts were then employed directly in the appropriate couplings.

N-{[5-(Aminomethyl)thien-3-yl]methyl}pyridin-2-amine (trifluoroacetate) (55)

-   a) A solution of tert-butyl (4-cyanothien-2-yl)methylcarbamate (7 g;     29.4 mmol) in 120 ml of ethanol was saturated with NH₃ and then     hydrogenated in the presence of Ra—Ni (9 g of aqueous suspension;     decanted with ethanol) under standard conditions. Filtration of the     reaction mixture, evaporation and chromatography of the resulting     residue on silica gel (CH₂Cl₂/CH₃OH plus aqueous NH₃) afforded 4.4 g     of the amine as yellowish oil. -   b) 1.2 g of the amine 55a (4.3 mmol), 0.6 g of ethyldiisopropylamine     and 15 g of 2-fluoropyridine were refluxed for 20 h. The residue     obtained after evaporation of the mixture was taken up in CH₂Cl₂,     washed with 0.1N HCl and saturated NaCl solutions, dried and again     evaporated.

1 g; ESI-MS [M+H⁺]=320.15.

-   c) 0.9 g of the Boc-protected amine 55b were dissolved in 10 ml of     CH₂Cl₂ and, after addition of 5 ml of TFA at 0° C., stirred at room     temperature for 1 h. Evaporation of the reaction mixture afforded     1.65 g of a brownish oil, which was reacted directly without further     purification (ESI-MS [M+H⁺]=220.05).

N¹-Methyl-N²-pyridin-2-ylethane-1,2-diamine (acetate) (56)

-   a) tert-Butyl 2-aminoethyl(methyl)carbamate (2.8 g; 16.1 mmol) and     19 ml of 2-fluoropyridine were refluxed for about 23 h. Evaporation     of the reaction mixture afforded 4 g of a brown oil (ESI-MS     [M+H⁺]=252.15) which was directly reacted further. -   b) 2 g of the crude product 56a were stirred in 30 ml of TFA at RT     overnight. The mixture was evaporated and purified by MPLC on RP     silica gel (CH₃CN/H₂O plus 0.1% acetic acid);

2.2 g; ESI-MS [M+H⁺]=152.1.

N-[4-(Aminomethyl)phenyl]-2-pyridinamine (57)

Preparation took place in analogy to 56 starting from tert-butyl 4-aminobenzylcarbamate. 38 mg of the title compound were isolated; ESI-MS [M+H⁺]=200.15.

N-[4-(Aminomethyl)phenyl]-N′-benzylurea (trifluoroacetate) (58)

-   a) Triethylamine (6.8 g, 67.12 mmol) and then, at 0° C.,     di-tert-butyl dicarbonate (18.6 g, 85.00 mmol) were added to     4-aminobenzylamine (10.0 g, 81.85 mmol) in 150 ml of CH₂Cl₂. The     mixture was stirred at 0° C. for 1 h and at RT for 2 h. For workup,     150 ml of a 1% aqueous citric acid solution were added, the phases     were separated, and the aqueous phase was back-extracted twice with     CH₂Cl₂ (150 ml). Renewed washing with H₂O, drying of the combined     organic phases with Na₂SO₄ and evaporation afforded a solid which     was stirred with a little diisopropyl ether, filtered off with     suction and dried.

13.0 g; ESI-MS [M+H⁺−^(t)Bu]=167.05.

¹H-NMR (360 MHz, CDCl₃) δ (ppm): 7.04 (2H, d), 6.61 (2H, d), 4.78 (1H, s br.), 4.17 (2H, d), 3.67 (2H, s br.), 1.46 (9H, s).

-   b) Benzyl isocyanate (2.40 g, 18.00 mmol) was added to a solution of     the protected amine 58a (4.0 g, 17.99 mmol) and triethylamine (1.82     g, 18.00 mmol) in 220 ml of 10:1 toluene/DMF while cooling in ice.     The reaction mixture was stirred at RT overnight. It was possible     for part of the urea which had formed to be filtered off directly as     precipitate and dried. The filtrate was washed twice with H₂O,     dilute tartaric acid to pH 3 and again twice with H₂O to pH 5, and     the organic phase was then dried and evaporated. A total of 6.0 g     was obtained in this way; ESI-MS [M+H⁺−^(t)Bu]=300.15. -   c) The urea 58b obtained in this way was introduced into 90 ml of     CH₂Cl₂ and, at 0° C., TFA (2.24 g, 196.25 mmol)—dissolved in 90 ml     of CH₂Cl₂—was added dropwise. After 3 h, a further 1 ml of TFA was     added, and the mixture was then stirred at RT overnight. Addition of     a further 1 ml of TFA was followed by stirring for 5 h, and then the     mixture was poured into ice-water and extracted with ethyl acetate     (2×50 ml). The aqueous phase was basified with 2N NaOH solution and     extracted with CH₂Cl₂ (2×50 ml). The insoluble portion between the     phases was filtered off and dried.

4 g; ESI-MS [2M+H⁺]=511.35.

¹H-NMR (200 MHz, DMSO) δ (ppm): 8.52 (1H, s), 7.39–7.07 (9H, m), 6.62 (1H, t), 4.27 (2H, d), 3.61 (2H, s).

[4-(Aminomethyl)phenyl]guanidine (bishydrochloride) (59)

p-Aminobenzylamine (6.7 g; 54.84 mmol) was suspended in 20 ml of 6N HCl and, while refluxing, 5.3 g of cyanamide—dissolved in 5 ml of H₂O—were slowly added dropwise. After the reaction was complete, 50% NaOH solution was added to the solution at 0° C., and the resulting precipitate was filtered off with suction, boiled in 50 ml of ethanol and filtered. Concentration of the mother liquor and stirring of the resulting residue with diethyl ether afforded 1.4 g of yellow solid; m.p.: 255° C.

[4-(5-Chloro-1H-benzimidazol-2-yl)phenyl]methanamine (trifluoroacetate) (60)

Preparation took place in analogy to building block 14 by reaction with 4-chloro-1,2-diaminobenzene (104 mg); ESI-MS [M+H⁺]: 258.05, 129.6.

[4-(5,6-Dimethyl-1H-benzimidazol-2-yl)phenyl]methanamine (trifluoroacetate) (61)

Preparation took place in analogy to building block 14 by reaction with 4,5-diamino-o-xylene (230 mg); ESI-MS [M+H⁺]: 253.1, 252.1, 147.1, 126.6.

N-[2-(4-Piperidinyl)ethyl]-2-pyridinamine (tristrifluoroacetate) (62)

Synthesis took place in analogy to building block 56 starting from 2-(4-piperidinyl)ethanamine which was previously converted under standard conditions into the corresponding tert-butyl 2-(4-piperidinyl)ethylcarbamate. 251 mg of the title compound were isolated; ESI-MS [M-3CF₃COO-+H+]: 206.1, 103.7.

N-[2-(3-Pyrrolidinyl)ethyl]-2-pyridinamine (tristrifluoroacetate) (63)

Synthesis took place in analogy to building block 56 starting from 2-(3-pyrrolidinyl)ethanamine which was previously converted under standard conditions into the corresponding tert-butyl 2-(3-pyrrolidinyl)ethylcarbamate. 500 mg of the title compound were isolated; ESI-MS [M-3CF₃COO—+H⁺]: 192.15.

{4-[(3-Phenylpropanoyl)amino]phenyl}methanamine (hydro-chloride) (64)

-   a) 350 mg (1.66 mmol) of 3-phenylpropionic acid were dissolved in 20     ml of THF and, at 0° C., 1.24 g of DIPEA and 2.3 ml of 50%     propanephosphonic anhydride solution in THF were added. After 15     min, 350 mg (1.57 mmol) of tert-butyl 4-aminobenzylcarbamate in 5 ml     of THF were added dropwise, and the mixture was warmed to RT and     stirred for 16 h. It was concentrated, the residue was taken up in     70 ml of H₂O/ethyl acetate, and the organic phase was washed with     saturated NaHCO₃ solution, 1% citric acid and H₂O, dried and     concentrated (500 mg); ESI-MS [M+H⁺-t-butyl]=299. -   b) 880 mg (2.48 mmol) of the above compound were dissolved in 20 ml     of THF, and about 20 ml of HCl in diethyl ether (saturated at 0° C.)     were added. The solution was then stirred at RT for 2 d and the     resulting precipitate was filtered off and dried (700 mg); ESI-MS     [M+H⁺−NH₄ ⁺]=234.

(4-{[(Benzyloxy)carbonyl]amino}phenyl)methanamine (hydrochloride) (65)

-   a) 730 mg (3.28 mmol) of tert-butyl 4-aminobenzylcarbamate were     dissolved in 20 ml of THF and, after addition of a solution of 1.18     g of NaHCO₃ in 10 ml of water, cooled to 0° C. 590 mg of     benzyloxycarbonyl chloride were added dropwise to this mixture, and     it was stirred at RT overnight. The residue after concentration was     dissolved in 70 ml of H₂O/ethyl acetate, and the organic phase was     separated off and washed with saturated NaHCO₃ solution, 1% citric     acid and H₂O. Drying and concentration afforded 1.08 g; ESI-MS     [M+Na⁺]=379. -   b) The product from the previous stage was dissolved in 10 ml of     THF, and in 20 ml of HCl in diethyl ether (saturated at 0° C.) were     added. The solution was stirred overnight, and the resulting     crystals were filtered off with suction (800 mg); ESI-MS     [M+H⁺−NH₃]=240.

[11-(2-tert-Butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl]acetic acid (66)

Alkylation of tert-butyl (6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (4) with methyl bromoacetate in analogy to the synthesis of building block 1 afforded 13.8 g of a pale yellowish oil, which was directly hydrolyzed further with KOH in dioxane/H₂O (11.2 g); ESI-MS [M+H⁺−^(t)Bu]=326.15.

¹H-NMR (DMSO-d6, 360 MHz) diastereomer mixture: δ (ppm): 7.80–7.0 (m, 8H), 4.8–4.6 (m, 2H), 4.55 (m, 1H), 3.6–3.1 (broad m, overlapped by H₂O, 2H), 3.05 (m, 2H), 1.3/1.15 (s, 9H).

[6-(1H-Benzimidazol-2-yl)pyridin-3-yl]methanamine (bistrifluoroacetate) (67)

-   a) Preparation took place in analogy to 13 starting from tert-butyl     (6-cyanopyridin-3-yl)methylcarbamate (6.0 g, 25.72 mmol);     crystallization of the crude product from methanol afforded 5.15 g;     ESI-MS [M+H⁺]=325. -   b) 0.55 g of the Boc-protected amine 67a in 10 ml of CH₂Cl₂ were     mixed with 5 ml of TFA and stirred at RT for 2 h. Evaporation of the     reaction mixture afforded 0.95 g of a white solid; ESI-MS     [M+H⁺]=225.25.

N¹-Pyridin-2-ylpropane-1,3-diamine (68)

2-Bromopyridine (100 g; 0.633 mol) and 1,3-diaminopropane (234.5 g; 3.16 mol) were refluxed for 7 h. After the reaction was complete, the mixture was evaporated, and distillation of the remaining residue under oil pump vacuum afforded 43 g of the required product; ESI-MS [M+H⁺]=152.15.

¹H-NMR (360 MHz, CDCl₃) δ (ppm): 8.05 (d, 1H), 7.36 (t, 1H), 6.51 (t, 1H), 6.36 (d, 1H), 4.98 (s, 1H), 3.35 (s, 2H), 2.82 (t, 2H), 1.73 (m, 1H), 1.32 (s, 2H).

(11E/Z)-11-(3-Methoxy-3-oxopropylidene)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl acetate (69)

-   a) A suspension of 100 g (448 mmol) of     5H-dibenzo[b,e]azepine-6,11-dione in 2000 ml of toluene was added     dropwise to 448 ml of a 1.5 molar vinyl Grignard solution while     cooling in ice. The mixture was stirred at RT overnight and then 70     ml of ice-water were added, and precipitated salts were filtered off     with suction, dried and concentrated to half the original volume.     Filtration with suction and drying of the resulting precipitate     afforded a total of 64.2 g. -   b) A mixture of 39 g of 69a, 3 g of triphenylphosphine, 1 g of PdCl₂     and 40 ml of ethanol was treated with CO (550 to 650 bar) in a 300     ml autoclave at 80 to 100° C. for 20 h. The resulting precipate was     filtered off with suction, recrystallized from glacial acetic acid     and then stirred with CH₂Cl₂ (33 g; m.p.: >250° C.).

11-(3-Methoxy-3-oxopropyl)-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepin-5-yl acetate (70)

Hydrogenation of 69 in analogy to the preparation of 2 afforded 100 mg of methyl 3-[5-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]propanoate, which were then reacted with TFA to give the title compound (90 mg); ESI-MS [M+H⁺]=354.25.

(10E/Z)-10-(2-Methoxy-2-oxoethylidene)-4-oxo-4H-thieno[3,4-c][1]benzazepin-5 (10H)-yl acetate (71)

4H-Thieno[3,4-c][1]benzazepine-4,10 (5H)-dione (preparation described in EP 0209022; 0.9 g; 4.33 mmol) was reacted by a standard method with methyl diethyl phosphonoacetate and sodium methanolate as base in 100 ml, and purification of the crude product by chromatography on silica gel (CH₂Cl₂/CH₃OH 0 to 2%) and stirring in diethyl ether afforded 1.1 g. Alkylation with tert-butyl bromoacetate in analogy to 2 and subsequent ester cleavage with TFA afforded 85 mg of the title compound; ESI-MS [M+H⁺]=344.

10-(2-Methoxy-2-oxoethyl)-4-oxo-4H-thieno[3,4-c][1]benzazepin-5(10H)-yl acetate (72)

Hydrogenation of 71 in analogy to the preparation of 2 and subsequent TFA cleavage afforded the title compound (45 mg); ESI-MS [M+H⁺]=346.

(9E/Z)-9-(2-Methoxy-2-oxoethylidene)-5-oxo-9H-dithieno[3,4-b: 3,4-e]azepin-4 (5H)-yl acetate (73)

Synthesis took place in analogy to building block 71 starting from 9H-dithieno[3,4-b:3,4-e]azepine-5,9 (4H)-dione (preparation described in EP 0209773). 62 mg of the title compound were isolated; ESI-MS [M+H⁺]=350.

9-(2-Methoxy-2-oxoethyl)-5-oxo-9H-dithieno[3,4-b:3,4-e]azepin-4(5H)-yl acetate (74)

Hydrogenation of 73 in analogy to the preparation of 2 and subsequent TFA cleavage afforded the title compound (20 mg); ESI-MS [M+H⁺)=352.

2-{[11-(2-tert-Butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepin-5-yl]methyl]-1,3-thiazole-4-carboxylic acid (75)

-   a) Alkylation of 5 g (15.46 mmol) of tert-butyl     (6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate (4) with     bromoacetonitrile in analogy to 1 afforded 5.5 g of a brownish oil     (ESI-MS [M+H⁺]=363.15), which was reacted directly with H₂S in     pyridine with addition of triethylamine to give a thioamide. The     crude product obtained after workup was stirred with n-pentane (7     g). -   b) Reaction of the thioamide (4 g; 10.1 mmol) with ethyl     bromopyruvate in 30 ml with the addition of 0.83 g of KHCO₃ led to     ethyl     2-{[11-(2-tert-butoxy-2-hydroxypropyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl]methyl}-1,3-thiazole-4-carboxylate     (4.1 g; ESI-MS [M+H⁺]=493.15), of which 3 g were hydrolyzed with KOH     in dioxane/H₂O (2 g; ESI-MS [M+H⁺]=465.15).

Examples I.B Examples of the Synthesis of Compounds of the Formula I (B—G—L) Example I.B.1 6-Oxo-5-(2-oxo-2-{[2—(2-pyridinylamino)ethyl]amino}ethyl]11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate (15)

-   a)     11-(2-Methoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepin-5-yl     acetate 3 (0.45 g; 1.33 mmol) was dissolved in 25 ml of CH₂Cl₂ and,     at 0° C., 1.1 eq. of N′-(dimethylaminopropyl)-N-ethylcarbodiimide     (0.28 g) and 1.03 eq. of N-methylmorpholine (0.15 ml) were added.     After about 40 min., N-(2-pyridinyl)-1,2-ethanediamine (0.18 g; 1.33     mmol) was added and the mixture was stirred at RT. After the     reaction was complete (about 2 h), the mixture was diluted with     CH₂Cl₂, washed with saturated NaCl solution, dried and concentrated.     The remaining residue (0.49 g) was purified by chromatography on     silica gel (CH₂Cl₂/CH₃OH 3 to 10%).

0.36 g; ESI-MS [M+H+]459.

-   b) Methyl     [6-oxo-5-(2-oxo-2-{[2-(2-pyridinylamino)ethyl]-amino}ethyl)-6,11-dihydro-5H-di-benzo[b,e]azepin-11-yl-]acetate     (0.34 g; 0.74 mmol) was dissolved in 15 ml of CH₃OH and 2 ml of H₂O     and, after addition of a total of 2 eq. of KOH (0.085 g), heated to     reflux. After the reaction was complete, the mixture was evaporated,     and the resulting crude product was purified by MPLC (silica gel:     Bischoff Prontoprep 60–2540-C18E, 32 μm; eluent: CH₃CN/H₂O+0.1%     acetic acid) and then lyophilized.

0.11 g; ESI-MS [M+H⁺]=445.1;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 8.3 (m, 1H), 7.95 (m, 1H), 7.65–7.1 (m, 9H), 6.65–6.30 (m, 3H), 4.8–4.2 (m, 4H), 3.55–3.1 (m, 4H), 3.85 (1H).

Example I.B.2 6-Oxo-5-{2-oxo-2-[4-(2-pyridinyl)-1-piperazinyl]ethyl}-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate (16)

-   a)     11-(2-Methoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]-azepin-5-yl     acetate 3 (1.2 g; 3.54 mmol) was dissolved in 25 ml of CH₂Cl₂ and,     at 0° C., 1.1 eq. of N′-(dimethylaminopropyl)-N-ethylcarbodiimide     (0.8 g) and 1.0 eq. of DIPEA (ethyldiisopropylamine) (0.45 g) and,     after about 2 h, N-(2-pyridinyl)piperazine (0.57 g; 3.54 mmol) were     added. The mixture was then stirred at RT. After the reaction was     complete (about 2 h), the mixture was diluted with CH₂Cl₂, washed     with saturated NaCl solution, dried and concentrated. The remaining     residue (2.03 g) was purified by chromatography on silica gel     (CH₂Cl₂/CH₃OH 2 to 8%).

0.57 g; ESI-MS [M+H⁺]=485.25;

-   b) Methyl     (6-oxo-5-{2-oxo-2-[4-(2-pyridinyl)-1-piperazinyl]-ethyl}-6,     1-dihydro-5H-dibenzo-[b,e]azepin-1′-yl)acetate (0.485 g; 1.18 mmol)     was dissolved in 30 ml of 5:1 dioxane/H₂O and, after addition of 1.5     eq. of KOH (0.1 g), heated to reflux. After the reaction was     complete, the mixture was evaporated, and the resulting crude     product was purified by MPLC (silica gel: Bischoff Prontoprep     60–2540-C18E, 32 μm; eluent: CH₃CN/H₂O+0.1% acetic acid) and then     lyophilized.

0.21 g; ESI-MS [M+H⁺]=471.15;

-   -   ¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm)         12.2–11.8 (broad, 1H), 8.15 (m, 1H), 7.7–7.05 (m, 9H), 6.85 (m,         1H), 6.7 (m, 1H), 5.25–4.25 (4H), 3.75–3 (m, overlapped by H₂O),         2.85 (m, 1H).

Example I.B.3 5-[2-({[6-(1H-Benzimidazol-2-yl)-3-pyridinyl]methyl}amino)-2-oxoethyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate (17)

11-(2-Methoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]-azepin-5-yl acetate 3 (0.56 g; 1.66 mmol) was dissolved in 15 ml of CH₂Cl₂ and, at 0° C., 1.2 eq. of N′-(dimethylaminopropyl)-N-ethylcarbodiimide (0.37 g) and 4.4 eq. of DIPEA (0.95 g) were added. After about 50 minutes, 6-(1H-benzimidazol-2-yl)-3-pyridinyl]methanamine×2TFA (6) (0.94 g; 1.66 mmol)—dissolved in 15 ml of DMF—was added and stirred at RT. After the reaction was complete (about 2 h), the mixture was diluted with CH₂Cl₂, washed with saturated NaCl solution, dried and concentrated. The resulting crude product (1.4 g) was reacted directly without further purification.

ESI-MS [M+H⁺]=546.25.

Methyl {5-[2-({[6-(1H-benzimidazol-2-yl)-3-pyridinyl]methyl}-amino)-2-oxoethyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetate (1.4 g) was dissolved in 30 ml of 5:1 dioxane/H₂O and, after addition of 2.15 eq. of KOH (0.2 g), heated to reflux. After the reaction was complete (12 h), the mixture was evaporated, and the resulting crude product was purified by MPLC (silica gel: Bischoff Prontoprep 60–2540-C18E, 32 μm; eluent: CH₃CN/H₂O+0.1% acetic acid) and then lyophilized.

0.45 g; ESI-MS [M+H+]532.15

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 12.9 (s, 1H), 8.95 (m, 1H), 8.70 (m, 1H), 8.30 (m, 1H), 7.85 (m, 1H), 7.8–7.05 (m 12H), 4.85–4.25 (m, 4H), 3.75–3.0 (m, overlapped by H₂O), 2.90 (m, 1H).

The following were prepared analogously:

Example I.B.4 10-Oxo-11-[2-oxo-2-({4-[(2-pyridinylamino)methyl]benzyl}amino)-ethyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl acetate (18)

Coupling with N-[4-(aminomethyl)benzyl]-2-pyridinamine (12) and subsequent hydrolysis of the methyl ester afforded 0.3 g;

ESI-MS [M+H⁺]=521.25;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 8.70 (m, 1H), 7.95 (m, 1H), 7.70–6.95 (m, 15H), 6.45 (m, 2H), 4.85–4.2 (m 8H), 2.8 (m 1H).

Example I.B.5 5-(2-{[2-(4,5-Dihydro-1H-imidazol-2-ylamino)ethyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate (19)

Coupling with N¹-(4,5-dihydro-1H-imidazol-2-yl)-1,2-ethanediamine and subsequent hydrolysis of the methyl ester afforded 0.42 g;

ESI-MS [M+H⁺]=436.1;

Example I.B.6 2-{5-[({[11-(Carboxymethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]25 azepin-5-yl]acetyl}amino)methyl]-2-pyridinyl}-4,5-dihydro-1H-imidazol-1-ium acetate (20)

Coupling with 2-[5-(aminomethyl)-2-pyridinyl]-4,5-dihydro-1H-imidazole and subsequent hydrolysis of the methyl ester afforded 0.3 g as acetate;

ESI-MS [M+H⁺]=502.15;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 9.15–8.80 (m, 2H), 8.65 (m, 1H), 8,1–7.05 (m 10H), 4.8–3.75 (m, overlapped by H₂O), 3.4 (m 2H), 2.80 (m, 2H), 1.85 (s, 3H).

Example I.B.7 6-Oxo-5-[2-oxo-2-({[1-(2-pyridinyl)-4-piperidinyl]methyl}amino)-ethyl]-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate (21)

Coupling with [1-(2-pyridinyl)-4-piperidinyl]methanamine and subsequent hydrolysis of the methyl ester afforded 0.4 g;

ESI-MS [M+H⁺]499.25;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 12.15 (broad), 8.2 (m 1H), 8.15 (m 1H), 7.75–7.05 (m, 9H), 6.85 (m 1H), δ 6.6 (m, 1H), 4.8–4.2 (m 4–5H), 3.65–2.7 (m, overlapped by H₂O), 1.70 (m 3H), 1.2 (m, 2H).

Example I.B.8 2-[({[11-(Carboxymethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]10 azepin-5-yl]acetyl}amino)methyl]-1H-benzimidazol-1-ium acetate (22)

Coupling with 1H-benzimidazol-2-ylmethanamine and subsequent hydrolysis of the methyl ester afforded 0.48 g as acetate;

ESI-MS [M+H⁺]=455.15;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 12.1 broad, 8.95 (m 1H), 7.75–7.05 (m 12H), 4.85–4.30 (m, 6H), 2.85 (m 1H), 1.95 (s, 3H).

Example I.B.9 2-[({(11-(Carboxymethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]-azepin-5-yl}acetyl}amino)methyl]-3H-imidazo[4,5-b]pyridin-3-ium acetate (23)

Coupling with 2-(aminomethyl)-3H-imidazo[4,5-b]pyridine and subsequent hydrolysis of the methyl ester afforded 0.24 g as acetate;

ESI-MS [M+H⁺]=456.15;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 9.8/9.25 (broad), 8.25 (m 1H), 7.95 (m 1H), 7.65–6.8 (m 8–9H), 4.75–4.40 (m 4H), 4.0–2.9 (m, overlapped by H₂O), 1.80 (s, 3H).

Example I.B.10 6-Oxo-5-(3-oxo-3-{[2-(2-pyridinylamino)ethyl]amino}propyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate (24)

Coupling of 3-[11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro 5H-dibenzo[b,e]azepin-5-yl]propanoic acid (6), subsequent cleavage of the tert-butyl ester with TFA and purification by MPLC afforded 40 mg;

ESI-MS [M+H⁺]459.15;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 8.15 (in 1H), 7.95 (m 1H), 7.70–7.15 (m, 1H), 6.65 (broad, 1H), 6.45 (m 2H), 4.70 (m 1H), 4.40 (m 2H), 4.25–2.6 (m, overlapped by H₂O).

Example I.B.11 6-Oxo-5-{3-oxo-3-[4-(2-pyridinyl)-1-piperazinyl]propyl}-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate (25)

85 mg were obtained in analogy to Example 10;

ESI-MS [M+H+)=485.25;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm)) 8.15 (m, 1H), 7.5–7.05 (m 9H), 6.85 (m 1H), 6.70 (m 1H), 4.85–3.85 (m, 4H), 3.65–3.15 (m, overlapped by H₂O), 3.05–2.7 (m 3H).

Example I.B.12 {5-[3-({[4-(1H-Benzimidazol-2-yl)-2-thienyl]methyl}amino)-3-oxopropyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}-acetic acid (26)

20 mg were obtained in analogy to Example 10;

ESI-MS [M+H⁺]=551.15;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 12.2 (broad), 8.70 (m 1H), 8.10 (m, 1H), 7.80–6.95 (m, 13H), 4.70 (m 1H), 4.60–3.90 (m, 5H), 3.55–2.85 (m, overlapped by H₂O).

Example I.B.14 2-{[(1-{[11-(Carboxymethyl)-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepin-5-yl]acetyl}-4-piperidinyl)methyl]amino}pyridinium acetate (28)

Coupling with N-(4-piperidinylmethyl)-2-pyridinamine and subsequent hydrolysis of the methyl ester afforded 65 mg;

ESI-MS [M+H⁺]=499.25;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 8.05 (m, 1H), 7.80–7.15 (m, 9H), 6.70 (m, 1H), 6.55 (m, 2H), 5.35–4.80 (m 3H), 4.70–4.0 (m, 3H), 3.75–2.80 (m, overlapped by H₂O), 2.05 (s, 3H), 2.80 (m, 3H), 1.25 (m 2H).

Example I.B.15 5-(2-{4-[(Benzylamino)carbonyl]-1-piperazinyl}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate (29)

-   a)     11-(2-Methoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]-azepin-5-yl     acetate 3 (2.5 g; 7.37 mmol) was dissolved in 40 ml of CH₂Cl₂ and     “preactivated”—as described above—by adding 1.2 eq. of     N′-(dimethylaminopropyl)-N-ethylcarbodiimide (1.15 g) and 1.2 eq. of     DIPEA (1.15 g). After 1 h, Boc-piperazine (1.37 g) was added, and     the mixture was stirred at 0° C. for 1 h and then at RT. For workup,     the mixture was diluted with CH₂Cl₂, washed with saturated NaCl     solution, dried and concentrated. The resulting crude product     (3.2 g) was purified by chromatography on silica gel (CH₂Cl₂/CH₃OH 1     to 3%+0.1% acetic acid).

1.7 g; ESI-MS [M+H+]=508.2;

-   b)     5-{2-[4-(tert-Butoxycarbonyl)-1-piperazinyl]-2-oxoethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl     acetate (1.7 g) was dissolved in 20 ml of CH₂Cl₂ and, at 0° C., 10     ml of TFA were added. After the reaction was complete, the mixture     was concentrated and coevaporated 2× with toluene (1.75 g; ESI-MS     [M+H+]=408.15).

The TFA salt was then dissolved in 30 ml of 1:1 toluene/dioxane and, after addition of 2 eq. of DIPEA (0.4 g) and 1 eq. of benzyl isocyanate (0.2 g), heated to reflux. After the reaction was complete, the mixture was concentrated, taken up in CH₂Cl₂, washed with 1N HCl solution and then saturated NaCl solution, dried and evaporated (0.81 g; ESI-MS [M+H+]=541.25). Hydrolysis was effected by dissolving in 25 ml of 2:1 dioxane/H₂O, adding 1.5 eq. of KOH (0.13 g) and heating to reflux. The mixture was then concentrated, acidified with 2N HCl and extracted 2× with CH₂Cl₂. The combined organic phases were then washed with saturated NaCl solution, dried and again concentrated, and the resulting residue was stirred with methyl tert-butyl ether.

0.36 g; ESI-MS [M+H+]=527.15;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 7.7–7.1 (m, 14H), 5.25–4.1 (4H), 3.7–3.1 (m, overlapped by H₂O), 2.95 (m, 1H).

Example I.B.16 5-[2-({[5-(1H-Benzimidazol-2-yl)-2-thienyl]methyl}amino)-2-oxoethyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate (30)

-   a)     11-(2-Methoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepin-5-yl     acetate 3 (4 g; 11.8 mmol) was dissolved in 30 ml of CH₂Cl₂ and     “preactivated”—as described above—by adding 1.15 eq. of     N′-(dimethylaminopropyl)-N-ethylcarbodiimide (2.6 g) and 1.6 eq. of     DIPEA (2.5 g). After 1 h, 5-(aminomethyl)-3-thiophenecarbonitrile     (1.92 g)—dissolved in 35 ml of DMF—and a further 1 ml of DIPEA were     added, and the mixture was stirred at 0° C. for 1 h and then at RT.     The usual workup afforded 6.6 g of yellow oil which was purified by     chromatography on silica gel (CH₂Cl₂/CH₃OH 1 to 3%). 4.1 g; ESI-MS     [M+H+]=460.15; -   b) Methyl     [10-(2-{[(5-cyano-2-thienyl)methyl]amino}-2-oxoethyl)-11-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl]acetate     (0.85 g; 1.85 mmol) was dissolved in 15 ml of pyridine and, at 0°     C., 1.76 g of triethylamine were added, and H₂S was passed in for 90     minutes. After 1 h at RT, the reaction mixture was concentrated, and     CH₂Cl₂ was added and reevaporated 2× (0.9 g of yellow foam).     -   The thioamide was then dissolved in 20 ml of CH₂Cl₂ and, after         addition of 5 eq. of CH₃I (1.3 g), stirred at RT overnight. The         mixture was evaporated, and the residue was taken up in 25 ml of         CH₃OH, mixed with 1,2-phenylenediamine (0.197 g) and stirred at         RT for 3 h. Concentration of the mixture afforded 1.35 g of         crude product which was purified by chromatography on silica gel         (CH₂Cl₂/CH₃OH). 0.46 g; ESI-MS [M+H+]=551.15.

Hydrolysis of the methyl ester took place in analogy to the examples already described in 20 ml of 3:1 dioxane/H₂O with 80 mg of KOH at RT. Workup and purification of the crude product by MPLC (silica gel: Bischoff Prontoprep 60–2540-C18E, 32 μm; eluent: CH₃CN/H₂O+0.1% acetic acid) afforded 0.22 g of the required product.

ESI-MS [M+H+]=537.15;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 8.85 (m, 1H), 7.75–7.2 (m, 14H), 4.85–4.3 (m, 6H), 3.5–3.1 (m, overlapped by H₂O), 2.95 (m, 1H).

Example I.B.17 (5-{2-[({4-[Amino(imino)methyl]-2-thienyl}methyl)amino]-2-oxoethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11′-yl)acetic acid (31)

Methyl-[5-(2-{[(4-cyano-2-thienyl)methyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-di-benzo-[b,e]azepin-11-yl]acetate and the corresponding thioamide were prepared in analogy to Example 16. Methyl {5-[2-({[4-(thiocarbamoyl)-2-thienyl]methyl}amino)-2-oxoethyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetate (2.3 g; 4.66 mmol) in 30 ml of CH₂Cl₂ was stirred with 5 eq. of CH₃I (3.3 g) at RT overnight. The mixture was evaporated, and the residue was taken up in 20 ml of CH₃OH, mixed with 0.27 g of ammonium acetate and again stirred overnight. Concentration of the mixture afforded 1.44 g of the crude product (ESI-MS [M+H+]=477.15).

The methyl ester was taken up in 10 ml of dioxane and, after addition of 15 ml of 2N HCl refluxed for 6 h. The mixture was then evaporated, and the resulting residue was purified by MPLC (silica gel: Bischoff Prontoprep 60–2540-C18E, 32 μm; eluent: CH₃CN/H₂O+0.1% acetic acid).

0.12 g; ESI-MS [M+H⁺]=463.05;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 10.5–9.1 (broad), 9.05/8.8 (m, 1H), 8.35 (m, 1H), 7.7–7.0 (m, 10H), 4.95–4.15 (m, 6H), 3.6–2.90 (m, overlapped by H₂O), 2.70 (m, 1H).

Example I.B.18 {5-[2-({[4-(1H-Benzimidazol-2-yl)-2-thienyl]methyl}amino)-2-oxoethyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetic acid (32)

Methyl [5-(2-{[(4-cyano-2-thienyl)methyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepin-11-yl]acetate (0.5 g; 1.09 mmol) in 30 ml of CH₃OH was refluxed with 0.2 ml of sodium methoxide solution (30% in CH₃OH) for 7 h. Then 0.2 g of 1,2-phenylenediamine bishydrochloride was added, and the mixture was again refluxed for about 8 h. After the reaction was complete, the mixture was concentrated and the remaining residue was purified by chromatography on silica gel (CH₂Cl₂/CH₃OH 1 to 3%).

0.13 g; ESI-MS [M+H⁺]=551.15;

Hydrolysis in 15 ml of 3:1 dioxane/H₂O with 1.5 eq. of KOH (0.02 g) and purification of the crude product by MPLC (silica gel: Bischoff Prontoprep 60–2540-C18E, 32 μm; eluent: CH₃CN/H₂O+0.1 acetic acid).

0.03 g; ESI-MS [M+H⁺]=537.15;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 9.0/8.8 (m, 1H), 8.15 (m, 1H), 7.75–7.0 (m, 14H), 4.85–4.20 (m, 6H), 3.75–2.8 (m, overlapped by H₂O).

Example I.B.19 {5-[2-({[4-(3H-Imidazo[4,5-b]pyridin-2-yl)-2-thienyl]methyl}-amino)-2-oxoethyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetic acid (33)

Analogously by reaction with 2,3-pyridinamine.

32 mg; ESI-MS [M+H⁺]=538.4;

¹H-NMR (200 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 8.95–8.8 (m, 1H), 8.0 (m, 1H), 7.8–7.05 (m, 13H), 4.75–4.1 (m, 6H), 2.95 (m, 1H).

Example I.B.20 [5-(2-{[4-(1H-Benzimidazol-2-yl)benzyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid hydrochloride (34)

Analogously by reaction with 4-(1H-benzimidazol-2-yl)benzylmethylamine from building block 14.

40 mg; ESI-MS [M+H⁺]=531.15

¹H-NMR (400 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 8.95–8.8 (m, 1H), 8.0 (m, 1H), 7.8–7.05 (m, 13H), 4.75–4.1 (m, 6H), 2.95 (m, 1H).

Example I.B.21 {5-[2-({[4-(1H-benzimidazol-2-yl)-1,3-thiazol-2-yl]methyl-amino)-2-oxoethyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetic acid (35)

Analogously by reaction with [4-(1H-benzimidazol-2-yl)-1,3-thiazol-2-yl]methylamine.

430 mg; ESI-MS [M+H⁺]=538.15;

¹H-NMR (360 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 9.4/9.3 (m, 1H), 8.9 (m, 1H), 7.8–7.15 (m, 13H), 4.95–4.35 (m, 5H), 3.2 (m, overlapped by H₂O), 2.95 (m, 1H).

Example I.B.22 (5-(2-(4-(1H-Benzimidazol-2-yl)anilino)-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetic acid (36)

Analogously by reaction with 4-(1H-benzimidazol-2-yl)aniline.

100 mg; ESI-MS [M+H⁺]=517.15;

¹H-NMR (360 MHz; DMSO-d6) diastereomer mixture: δ (ppm) 12.75 (broad), 10.6 (m, 1H), 8.2 (m, 2H), 7.9–7.1 (m, 14H), 4.8–4.75 (m, 2H), 4.4 (m, 1H), 3.75–3.0 (m, overlapped by H₂O), 2.8 (m, 1H).

Example I.B.23 Methyl [10-(2-{[4-(1H-benzimidazol-2-yl)benzyl]amino}-2-oxoethyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl]acetate

[5-(2-Methoxy-2-oxoethyl)-11-oxo-5,11-dihydro-10H-dibenzo-[b,e][1,4]diazepin-10-yl]acetic acid 37c (0.8 g; 2.35 mmol) was dissolved in 50 ml of DMF and, at 0° C., 1.05 g of HATU and 0.3 g of DIPEA were added, and the mixture was stirred at RT for 30 min. Addition of [4-(1H-benzimidazol-2-yl)phenyl]methanamine bistrifluoracetate from building block 14 (1.06 g; 2.35 mmol) and 0.6 g of DIPEA was followed by stirring at 5° C. for 2 h. The mixture was diluted with CH₂Cl₂, washed with H₂O, dried and concentrated. Chromatography on silica gel (CH₂Cl₂/CH₃OH 1→8%) afforded 1.3 g of a pale brownish oil (ESI-MS [M+H⁺]=546.

¹H-NMR (400 MHz; DMSO-d6): δ (ppm) 8.45 (t, 1H), 8.15 (d, 2H), 7.05–7.7 (m, 16H), 4.75 and 4.65 (each d, 2H), 4.45–4.55 (m, 2H), 3.55 (s, 3H).

Example I.B.24 [10-(2-{[4-(1H-Benzimidazol-2-yl)benzyl]amino}-2-oxoethyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl]acetic acid (acetate)

Methyl [10-(2-{[4-(1H-benzimidazol-2-yl)benzyl]amino}-2-oxoethyl)-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-5-yl]acetate (1 g; 1.56 mmol) and 0.15 g of KOH were refluxed in 30 ml of 2:1 dioxane/H₂O for 3 h. Concentration of the mixture and chromatography of the crude product by MPLC (silica gel: Bischoff Prontoprep 60–2540-C₁₈E, 32 μm; eluent: CH₃CN/H₂O+0.1% acetic acid) afforded 0.22 g of the required product as acetate; ESI-MS [M+H⁺]532.

¹H-NMR (400 MHz; DMSO-d₆): δ (ppm) 12.75 (s br, 1H), 8.40 (t, 1H), 8.15 (d, 2H), 7.15–7.7 (m, 16H), 4.75 and 4.60 (each d, 2H), 4.45–4.55 (m, 2H), 2.1 (s, 3H).

Example I.B.25 Methyl [10-(2-{[(2-{[(benzylamino)carbonyl]amino}-1,3-thiazol-4-yl)methyl]amino}-2-oxoethyl)-11-oxo-10,11-dihydro-5H-dibenzo-[b,e][1,4]diazepin-5-yl]acetate

Preparation took place in analogy to I.B.23 by reacting [5-(2-methoxy-2-oxoethyl)-11-oxo-5,11-dihydro-10H-dibenzo[b,e]-[1,4]diazepin-10-yl]acetic acid 37c with N-[4-(aminomethyl)1,3-thiazol-2-yl]-N′-benzylurea (hydrochloride) (38). Chromatography on silica gel (CH₂Cl₂/CH₃OH 2→10%) afforded 0.45 g; ESI-MS [M+H⁺]=585.25.

Example I.B.26 [10-(2-{[(2-{[(Benzylamino)carbonyl]amino}-1,3-thiazol-4-yl)-methyl]amino}-2-oxoethyl)-11-oxo-10,11-dihydro-5H-dibenzo-[b,e][1,4]diazepin-5-yl]acetic acid

Hydrolysis of the methyl ester in analogy to I.B.24 and purification of the crude product by MPLC afforded 0.11 g;

ESI-MS [M+H⁺]=571.25.

Example I.B.27 [10-(2-{[(2-{[Amino(imino)methyl]-[10-(2-{[(2-{[Amino(imino)methyl}amino}-1,3-thiazol-5-yl)methyl]-diazepin-5-yl}acetic acid

Reaction in analogy to I.B.23 with [4-(aminomethyl)-1,3-thiazol-2-yl]guanidine (bishydrochloride) (39) afforded 0.09 g;

ESI-MS [M+H⁺]=535.15.

Example I.B.28 [5-(2-{[3-(1H-Imidazol-2-ylamino)-3-oxopropyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

-   a) 440 mg (1.3 mmol) of     11-(2-methoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]-azepin-5-yl     acetate (3) were dissolved in 15 ml of DMF, and 0.3 ml of DIPEA and     543 mg of HATU were added. After 30 min at room temperature,     3-amino-N-(1H-imidazol-2-yl)propanamide 42 (200 mg, 1.3 mmol)     dissolved in DMF was slowly added dropwise, and the mixture was     stirred for 6 h. It was taken up in ethyl acetate and water and     shaken 3× with H₂O and 3× with NaHCO₃ solution. The organic phase     was dried and concentrated, and the remaining residue was dissolved     in CH₂Cl₂/CH₃OH 19:1 and precipitated with diethyl ether. The     precipitate was filtered off with suction, washed and dried (220     mg). ESI-MS [M+H⁺]=476. -   b) I.B.28a was dissolved in 5 ml of THF, and a solution of 45 mg of     LiOH (1.89 mmol) in aqueous solution was added. The mixture was     stirred at RT until the reaction was complete and was then acidified     with 10% citric acid and concentrated. A white precipitate separated     out and was filtered off with suction, washed 4× with H₂O and dried     in vacuo (120 mg);

ESI-MS [M+H⁺]=462.

Example I.B.29 (5-{2-[4-({(Benzylamino)carbonyl]amino}methyl)piperidin-1-yl]-2-oxoethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetic acid

-   a) Coupling of     11-(2-Methoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl]     acetate (3) with N-benzyl-N′-(piperidin-4-ylmethyl)carbamate (THL     31, 47, 1990, 6903) in analogy to Example I.B.1 and subsequent     purification afforded 1.65 g, which were then hydrogenated under     standard conditions with 5% Pd on active carbon in 20 ml of CH₃COH     and addition of 1.35 ml of 2 N HCl (1.04 g). -   b) Reaction of the free amine (0.21 g) with 0.06 g of benzyl     isocyanate and 0.046 g of N-methylmorpholine in 15 ml of CH₂Cl₂     under reflux, washing of the mixture with aqueous 1 N HCl and     saturated NaCl solution and concentration afforded 0.17 g of a     yellowish oil; ESI-MS [M+H⁺]=569.25. -   C) Hydrolysis of the methyl ester under standard conditions in     analogy to I.B.1 and the usual workup afforded 0.16 g as a white     solid foam; ESI-MS [M+H⁺]=555.25.

The following were prepared in analogy to Example I.B.10:

Example I.B.30 6-Oxo-5-(3-oxo-3-{[(1-pyridin-2-ylpiperidin-4-yl)methyl]-amino}propyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 3-[11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl]propanoic acid 6 with [1-(2-pyridinyl)-4-piperidinyl]methanamine, subsequent cleavage of the tert-butyl ester with TFA and purification by MPLC afforded 106 mg; ESI-MS [M+H⁺]=513.25.

Example I.B.31 5-{3-[({1-[(Benzylamino)carbonyl]piperidin-4-yl}methyl)-amino]-3-oxopropyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling with 4-(aminomethyl)-N-benzylpiperidine-1-carboxamide (43), cleavage of the tert-butyl ester with TFA and purification by MPLC afforded 0.46 g; ESI-MS [M+H⁺]=569.25.

Example I.B.32 5-[3-({[5-(1H-Benzimidazol-2-yl)thien-2-yl]methyl}amino)-3-oxopropyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling with [5-(1H-benzimidazol-2-yl)thien-2-yl]methanamine (45), cleavage of the tert-butyl ester with TFA and purification by MPLC afforded 70 mg; ESI-MS [M+H⁺]=551.15.

Example I.B.33 5-[3-({[4-(1H-Benzimidazol-2-yl)thien-2-yl]methyl}amino)-3-oxopropyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling with (4-(1H-benzimidazol-2-yl)thien-2-yl]methanamine (44), cleavage of the tert-butyl ester with TFA and purification by MPLC afforded 20 mg; ESI-MS [M+H⁺]=551.15.

The following were prepared in analogy to Example I.B.1:

Example I.B.34 5-[2-[({1-[(Benzylamino)carbonyl]piperidin-4-yl]methyl)amino]-2-oxoethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate Coupling of 11-(2-methoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-ylacetate (3) with 4-(aminomethyl)-N-benzylpiperidine-1-carboxamide (43), ester cleavage and subsequent purification resulted in 0.42 g as a solid foam;

ESI-MS [M+H⁺]=555.25.

Example I.B.35 5-(2-{[4-({[(Benzylamino)carbonyl]amino}methyl)benzyl]amino} 2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 3 with N-[4-(aminomethyl)benzyl]-N′-benzylurea (40), ester cleavage and subsequent purification resulted in 0.62 g as a solid foam.

¹H-NMR (DMSO-d6, 400 MHz) diastereomer mixture: δ (ppm) 7.70–7.10 (m, 13H), 6.65–6.5 (m, 2H), 4.75–4.65 (m, 2H), 4.5–4.2 (m, 5H), 3.55, 3.25 (each dd, 1H), 2.0–1.85 (m, 2H).

Example I.B.36 6-Oxo-5-{2-oxo-2-[4-(pyridin-2-ylamino)piperidin-1-yl]ethyl}-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 3 with 2-(piperidin-4-ylamino)pyridine (46), ester cleavage and subsequent purification resulted in 0.3 g as a solid foam; ESI-MS [M+H⁺]=485.15.

Example I.B.37 5-(2-{[4-(1H-Benzimidazol-2-ylamino)benzyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl acetate (66) with N-[4-(aminomethyl)-phenyl]-1H-benzimidazol-2-amine (hydrochloride) (47) using HATU as coupling reagent, ester cleavage with TFA and purification of the crude product by MPLC afforded 0.4 g; ESI-MS [M+H⁺]=546.25.

Example I.B.38 Methyl-[5-(2-{[4-(1H-benzimidazol-2-ylamino)benzyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

5-(2-{([4-(1H-Benzimidazol-2-ylamino)benzyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-ylacetate I.B.37(0.9 g; 0.16 mmol) was suspended in 5 ml of CH₃OH and, after dropwise addition of 0.02 ml of SOCl₂, stirred at RT for 48 h. For workup, the reaction mixture was evaporated and stirred with n-pentane (40 mg); ESI-MS [M+H⁺]=560.25.

Example I.B.39 5-(2-{[5-(1H-Benzimidazol-2-ylamino)pentyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 3 with N¹-(1H-benzimidazol-2-yl)pentane-1,5-diamine (hydrochloride) (48) using HATU as coupling reagent, cleavage of the methyl ester in analogy to Example I.B.1 and filtration of the resulting crude product through a Chromabond C₁₈ cartridge afforded 0.24 g; ESI-MS [M+H⁺]=525.6.

Example I.B.40 5-(2-{[4-(1H-Benzimidazol-2-ylamino)butyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-ylacetate (66) with N¹-(1H-benzimidazol-2-yl)butane-1,4-diamine (trifluoroacetate) (49) using HATU as coupling reagent, cleavage of the tert-butyl ester and purification of the resulting crude product by RP-MPLC afforded 94 mg; ESI-MS [M+H⁺]=512.25.

Example I.B.41 5-{2-[(3-{[(Benzylamino)carbonyl]amino}benzyl)amino]-2-oxoethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl acetate (66) with (3-{[(benzylamino)-carbonyl]amino}phenyl)methanamine (hydrochloride) (41), TFA cleavage and stirring of the resulting crude product with methyl tert-butyl ether/CH₃OH 19:1 afforded 0.61 g of slightly brownish solids; ESI-MS [M+H⁺]=563.25.

Example I.B.42 5-(2-{4-[(1H-Benzimidazol-2-ylamino)methyl]piperidin-1-yl}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-ylacetate (66) with N-(piperidin-4-ylmethyl)-1H-benzimidazol-2-amine (trifluoroacetate) (50), TFA cleavage and chromatography by RP-MPLC afforded 60 mg; ESI-MS [M+H⁺]=538.25.

Example I.B.43 6-Oxo-5-[2-oxo-2-({[2-(pyridin-2-ylamino)-1,3-thiazol-4-yl]-methyl}amino)ethyl]-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl acetate (66) with N-[4-(aminomethyl)-1,3-thiazol-2-yl]pyridin-2-amine (bishydrochloride) (51), TFA cleavage and chromatography by RP-MPLC afforded 65 mg;

ESI-MS [M+H⁺]=514.15.

Example I.B.44 6-Oxo-5-[2-oxo-2-({[2-(pyridin-2-ylamino)-1,3-thiazol-5-yl]-methyl}amino)ethyl]-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-ylacetate (66) with N-[5-(aminomethyl)-1,3-thiazol-2-yl]pyridin-2-amine (bishydrochloride) (52), TFA cleavage and chromatography by RP-MPLC afforded 170 mg; ESI-MS [M+H⁺]=514.15.

Example I.B.45 5-(2-{[(2-{[Amino(imino)methyl]amino}-1,3-thiazol-4-yl)methyl]-amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate (trifluoroacetate)

Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl acetate (66) with [4-(aminomethyl)-1,3-thiazol-2-yl]guanidine (bishydrochloride) (39), TFA cleavage and chromatography by RP-MPLC afforded 25 mg; ESI-MS [M+H⁺]=479.15.

Example I.B.46 5-(2-{[(2-{[Amino(imino)methyl]amino}-1,3-thiazol-5-yl)-methyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]-azepin-11-yl acetate

Coupling of 11-(2-tert-Butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]-azepin-5-yl acetate (66) with N-[5-(aminomethyl)-1,3-thiazol-2-yl]guanidine (dihydrochloride) (53) and TFA cleavage afforded 70 mg; ESI-MS [M+H⁺]=479.15.

Example I.B.47 5-[2-({2-[4-(1H-Benzimidazol-2-yl)phenyl]ethyl}amino)-2-oxo-ethyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl acetate (66) with 2-[4-(1H-benzimidazol-2-yl)phenyl]ethanamine from building block 54 and TFA cleavage afforded 35 mg; ESI-MS [M+H⁺]=545.25.

Example I.B.48 6-Oxo-5-{2-oxo-2-[({4-[(pyridin-2-ylamino)methyl]thien-2-yl}-methyl)amino]ethyl}-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-ylacetate (66) with N-{[5-(aminomethyl)-thien-3-yl]methyl}pyridin-2-amine (trifluoroacetate) (55) and TFA cleavage afforded 170 mg; ESI-MS [M+H⁺]=527.25.

Example I.B.49 5-(2-{methyl-[2-(pyridin-2-ylamino)ethyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]-azepin-5-ylacetate (66) with N¹-methyl-N²-pyridin-2-ylethane-1,2-diamine (acetate) (56), TFA cleavage and RP-MPLC afforded 130 mg; ESI-MS [M+H⁺]=459.25.

Example I.B.50 6-Oxo-5-(2-oxo-2-[4-(2-pyridinylamino)benzyl]amino}ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 3 with N-[4-(aminomethyl)phenyl]-2-pyridinamine (57), cleavage of the methyl ester in analogy to Example I.B.1 and filtration of the resulting crude product through a Chromabond C₁₈ cartridge afforded 3 mg; ESI-MS [M+K⁺]=545.3, [M+H⁺]=507.2, 326.0, 254.1.

Example I.B.51 Methyl (5-{2-[(4-{[(benzylamino)carbonyl]amino}benzyl)amino]-2-oxoethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl) acetate

Coupling of 3 with N-[4-(aminomethyl)phenyl]-N′-benzylurea (trifluoroacetate) (58) and purification of the crude product by chromatography on silica gel afforded 550 mg; ESI-MS [M+K⁺]=615.2, [M+H⁺]: 577.35.

Example I.B.52 (5-{2-[(4-{[(Benzylamino)carbonyl]amino}benzyl)amino]-2-oxoethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetic acid

Hydrolysis of the methyl ester from I.B.51 in analogy to I.B.1 and purification of the crude product by RP-MPLC afforded 174 mg;

ESI-MS [M+K⁺]=601.25, [M+H⁺]: 563.35.

Example I.B.53 {4-[([11-(Carboxymethyl)-6-oxo-6,11′-dihydro-5H-dibenzo[b,e]45 azepin-5-yl]acetyl}amino)methyl]anilino}(imino)methanamine (trifluoroacetate)

Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-ylacetate (66) with [4-(aminomethyl) phenyl]guanidine (bishydrochloride) (59), TFA cleavage and purification of the crude product by RP-MPLC afforded 7.8 mg;

ESI-MS [M+K⁺]=510.1, [M+H⁺]=472.15.

Example I.B.54 [5-(2-{[4-(5-Chloro-1H-benzimidazol-2-yl)benzyl]amino}-2-oxo-ethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

Coupling of 3 with [4-(5-chloro-1H-benzimidazol-2-yl)phenyl]-methanamine (trifluoroacetate) (60) and cleavage of the methyl ester in analogy to I.B.1 afforded 25 mg; ESI-MS [M+H⁺]: 565.25.

Example I.B.55 [5-(2-{[4-(5,6-Dimethyl-1H-benzimidazol-2-yl)benzyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

Coupling of 3 with [4-(5,6-dimethyl-1H-benzimidazol-2-yl)phenyl]methanamine (trifluoroacetate) (61) and cleavage of the methyl ester in analogy to Example I.B.1 afforded 100 mg; ESI-MS [M+H⁺]: 559.25.

Example I.B.56 [6-Oxo-5-(2-oxo-2-{[3-(2-pyridinylamino)propyl]amino}ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

Coupling of 3 with N¹-(2-pyridinyl)-1,3-propanediamine (68) and cleavage of the methyl ester in analogy to Example I.B. afforded 8 mg; ESI-MS [M+H⁺]: 459.25.

Example I.B.57 Methyl [6-oxo-5-(2-oxo-2-{4-[2-(2-pyridinylamino)ethyl]-1-piperidinyl}ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]-acetate

Coupling of 3 with N-[2-(4-piperidinyl)ethyl]-2-pyridinamine (trifluoroacetate) (62) afforded 140 mg; ESI-MS [M+H⁺]: 527.25.

Example I.B.58 [6-Oxo-5-(2-oxo-2-[4-[2-(2-pyridinylamino)ethyl]-1-piperidinyl}-ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

Hydrolysis of the methyl ester from Example I.B.57 with LiOH in ethanol/H₂O afforded 90 mg; ESI-MS [M+K⁺]=551.2, [M+H⁺]: 513.25.

Example I.B.59 Methyl [6-oxo-5-(2-oxo-2-{3-[2-(2-pyridinylamino)ethyl]-1-pyrrolidinyl}ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]-acetate

Coupling of 3 with N-[2-(3-pyrrolidinyl)ethyl]-2-pyridinamine (trifluoracetate) (63) afforded 150 mg; ESI-MS [M+K⁺]=551.2, [M+H⁺]: 513.25.

Example I.B.60 [6-oxo-5-(2-oxo-2-{3-[2-(2-pyridinylamino)ethyl]-1-pyrrolidinyl}-ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

Hydrolysis of the methyl ester from Example I.B.59 afforded 150 mg; ESI-MS [M+K⁺]=537.2, [M+H⁺]: 499.25.

Example I.B.61 {6-Oxo-5-[2-oxo-2-({4-[(3-phenylpropanoyl)amino]benzyl}amino)-ethyl]-6,1′-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetic acid

Coupling of 3 with {4-[(3-phenylpropanoyl)amino]phenyl}-methanamine (hydrochloride) (64) and cleavage of the methyl ester in analogy to Example I.B.1 afforded 100 mg; ESI-MS [M+K⁺]=600.2, [M+H⁺]=562.2.

Example I.B.62 (5-{2-[(4-{{[(Benzyloxy)carbonyl]amino}benzyl)amino]-2-oxo-ethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetic acid

Coupling of 11-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-ylacetate (66) with (4-{[(benzyloxy)-carbonyl]amino}phenyl)methanamine (hydrochloride) (65) and TFA cleavage afforded 72 mg; ESI-MS [M+K⁺)=602.2, [M+H⁺]: 564.2, 308.0, 102.2.

Example I.B.63 (5-{2-[({5-[Amino(imino)methyl]-2-thienyl]methyl)amino]-2-oxo-ethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetic acid (acetate)

-   a) Coupling of 3 with 5-(aminomethyl)thiophene-2-carbonitrile     afforded 1.35 g of a yellowish oil (ESI-MS [M+H⁺]: 460.15). 1.25 g     of this amide in 15 ml of ethanol were mixed with 3 eq. of DIPEA and     2.5 eq. of hydroxylammonium chloride and stirred firstly at RT then     at 70° C. for 7 h. After addition of a further 1 eq. each of DIPEA     and hydroxylammonium chloride, the mixture was stirred at 50° C. for     4 h. The reaction mixture was then concentrated, diluted with methyl     tert-butyl ether and washed with water. The precipitate formed     thereby was filtered off with suction, taken up in CH₂Cl₂, again     washed with H₂O and evaporated. Stirring of the remaining residue     with ethanol/petroleum ether afforded 1 g of a white amorphous     solid.) -   b) Methyl     (5-{2-[({5-[(hydroxyamino)(imino)methyl]-3-thienyl}-methyl)amino]-2-oxoethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate     from I.B.63a was introduced into 10 ml of glacial acetic acid and,     after addition of 0.69 g of Zn dust, stirred at RT overnight. The     reaction mixture was then filtered through Celite and evaporated to     dryness (1.3 g);

ESI-MS [M+H⁺]: 477.15.)

-   c) Methyl ester I.B.63b (0.54 g) was mixed with 50 ml of 2 N HCl and     refluxed for 4 h. The mixture was then evaporated and the resulting     crude product was purified by RP-MPLC (60 mg);

ESI-MS [M+H⁺]=463.18.

Example I.B.64 [5-(5-{[(Benzylamino)carbonyl]amino}pentyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

-   a) 3 g (10.13 mmol) of methyl     (6-oxo-5,6-dihydro-11H-dibenzo-[b,e]azepin-11-yl)acetate 4a in 100     ml of DMF were mixed with 1.12 g of potassium tert-butoxide and     stirred at RT for 30 min. Then 2.95 g of     2-(5-bromopentyl)-1H-isoindole-1,3 (2H)-dione were added and the     mixture was stirred for 14 h. After the reaction was complete, the     mixture was poured into ice-water and extracted with ethyl acetate,     and the organic phase was washed 5× with saturated NaCl solution and     dried. The crude product obtained after evaporation was purified by     chromatography on silica gel (CH₂Cl₂) (3.5 g). -   b) Hydrolysis with hydrazine hydrate and the usual workup afforded     the free amine, which was likewise prepared by chromatography on     silica gel (CH₂Cl₂/CH₃OH 0 to 10%). Subsequent reaction with benzyl     isocyanate in 55 ml of toluene/DMF 10:1 and the usual workup     afforded 260 mg;

ESI-MS [M+H⁺]=500.25.

-   c) Hydrolysis of the methyl ester under standard conditions afforded     10 g of the title compound; ESI-MS [M+K⁺]=524.3, [M+H⁺]=486.2,     243.6.

Example I.B.65 Methyl (5-{2-[(4-aminobenzyl)oxy]ethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate (hydrochloride)

-   a) Methyl (6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-yl)acetate 4a     (10 g; 35.55 mmol)—dissolved in 200 ml of THF was slowly added     dropwise to 36 mmol of lithium diisopropylamide in 200 ml of THF at     0° C. and then stirred at 0° C. for 1 h. Subsequently about 100 ml     of ethylene oxide were added, and the reaction mixture was stored at     about 10° C. overnight. The next day, a further approx. 50 ml of     ethylene oxide were added, and the mixture was stirred under     autogenous pressure at RT for 48 h. For workup, the mixture was     poured into saturated NH₄Cl solution and extracted with ethyl     acetate and the organic phase was washed with 1 NHCl and then with     H₂O. The crude product obtained after drying and concentration was     purified by chromatography on silica gel (n-heptane/ethyl acetate 0     to 30%) (4 g); ESI-MS [M+H⁺]=326. -   b) A solution of the alcohol I.B.65a (3.2 g; 9.84 mmol) in 50 ml of     DMF was added dropwise to a suspension of 0.4 g of NaOH (60%; oil     removed with n-pentane) in 100 ml of DMF at 0° C., and the mixture     was stirred for about 1 h for complete formation of the anion. Then     9.5 g of 4-nitrobenzyl bromide—dissolved in 50 ml of DMF—were added,     and the mixture was stirred at RT for 48 h. For workup, the mixture     was poured into saturated NH₄Cl solution and extracted with ethyl     acetate, and the organic phase was washed 5× with saturated NaCl     solution. The crude product obtained after drying and concentration     was purified by chromatography on silica gel (n-heptane/ethyl     acetate 0 to 30%) (0.8 g). -   c) Reduction of the nitro compound I.B.65b (0.65 g; 1.41 mmol) with     H₂ and 10% Pd on active carbon in 100 ml of CH₃OH afforded after the     workup 650 mg of the title compound;

ESI-MS [M+K⁺]=469.1, [M+Na⁺]=453.15, [M+H⁺]=431.25, 236.6, 216.15.

Example I.B.66 Methyl (5-{2-[(4-{[(benzylamino)carbonyl]amino}benzyl)oxy]ethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetate

0.65 g (1.51 mmol) of the methyl ester I.B.65 were converted with 0.23 g of benzyl isocyanate and 0.17 g of triethylamine in 100 ml of CH₂Cl₂ into the corresponding benzylurea (purification of the crude product by chromatography on silica gel (CH₂Cl₂/ethanol)).

Hydrolysis of the ester in analogy to I.B.1 afforded 22 mg of the title compound; ESI-MS [M+K⁺]=588.3, [M+H⁺]=550.25.

Example I.B.67 Methyl {5-[4-(4-{[(benzylamino)carbonyl]amino}phenyl)butyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetate

-   a) A solution of methyl     (6-oxo-5,6-dihydro-11H-dibenzo[b,e]-azepin-11-yl)acetate 4a (0.2 g;     0.72 mmol) in 10 ml of DMF was added dropwise to a suspension of 0.3     g of NaH (60%; oil removed with n-pentane) in 30 ml of DMF at 0° C.,     and the mixture was then stirred for 1 h for complete formation of     the anion. The mixture was subsequently heated to 75° C., and a     solution of 4-(4-nitrophenyl)butyl methanesulfonate (0.2 g) in DMF     was added. The mixture was stirred at 75° C. for 3 h and, for     workup, then poured into saturated NH₄Cl solution and extracted with     ethyl acetate, and the organic phase was washed 4× with saturated     NaCl solution and concentrated. Alkaline extraction of the crude     product obtained in this way afforded 130 mg of methyl     {5-[4-(4-nitrophenyl)-butyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl}acetate;     ESI-MS [M+H⁺]=445. -   b) Reduction of the nitro compound in analogy to I.B.65 afforded the     corresponding amine (56 mg: ESI-MS [M+H⁺]=415), which was then     converted in analogy to I.B.66 with 0.02 g of benzyl isocyanate and     0.015 g of triethylamine into the benzylurea. Purification of the     crude product by chromatography on silica gel afforded 5 mg; ESI-MS     [M+K⁺]=586.2, [M+H⁺]: 548.3, 274.6.

Example I.B.68 N-{4-[({[5-(carboxymethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]-azepin-11-yl]acetyl}amino)methyl]phenyl}-1H-benzimidazol-2-amine (hydrochloride)

-   a) 0.5 g (1.26 mmol) of methyl     [5-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetate (2)     was hydrolyzed by the standard method with LiOH in ethanol/H₂O to     give     [5-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic     acid. Coupling of the acid with     N-[4-(aminomethyl)phenyl]-1H-benzimidazol-2-amine     (hydrochloride) (47) using HATU as coupling reagent and     chromatography of the resulting crude product on silica gel     (CH₂/Cl₂/CH₃OH 0 to 2%) afforded 170 mg of     tert-butyl-[11-(2-{[4-(1H-benzimidazol-2-ylamino)benzyl]-amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin     5-yl]acetate; ESI-MS [M+H⁺]: 602. -   b) TFA cleavage, dissolving of the crude product in CH₂Cl₂ and     conversion into the corresponding hydrochloride (HCl in diethyl     ether; saturated at 0° C.) afforded 25 mg of the title compound;     ESI-MS [M+H⁺]: 546.2.

The following were prepared analogously:

Example I.B.69 [5-(2-{[3-(4-Methyl-1H-imidazol-1-yl)propyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

2 mg; ESI-MS [M+H⁺]447.

Example I.B.70 [5-(2-{[3-(4-Methyl-1-piperazinyl)propyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

4 mg; ESI-MS [M+H⁺]=465.

Example I.B.71 (6-Oxo-5-{2-oxo-2-[(3-pyridinylmethyl)amino]ethyl}-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetic acid

3 mg; ESI-MS [M+H⁺]=416.

Example I.B.72 [5-(2-{[3-(1H-Imidazol-1-yl)propyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

3 mg; ESI-MS [M+H⁺]=433.

Example I.B.73 [5-(2-{[1-Methyl-2-(4-morpholinyl)ethyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

3 mg; ESI-MS [M+H⁺]=452.

Example I.B.74 [5-(2-{[(1-Ethyl-2-pyrrolidinyl)methyl amino]-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetic acid

2 mg; ESI-MS [M+H⁺]=436.

Example I.B.75 (6-Oxo-5-{2-oxo-2-[4-(4-pyridinylmethyl)-1-piperazinyl]ethyl}-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

4 mg; ESI-MS [M+H⁺]=485.

Example I.B.76 [6-Oxo-5-(2-oxo-2-{4-[2-(1-pyrrolidinyl)ethyl]-1-piperazinyl}-ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

2 mg; ESI-MS [M+H⁺]=491.

Example I.B.77 [5-(2-{4-[2-(Diethylamino)ethyl]-1-piperazinyl}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

2 mg; ESI-MS [M+H⁺]=493.

Example I.B.78 [5-(2-{4-[2-(4-Morpholinyl)ethyl]-1-piperazinyl}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

4 mg; ESI-MS [M+H⁺]=507.

Example I.B.79 (6-Oxo-5-{2-oxo-2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl}-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetic acid

3 mg; ESI-MS [M+H⁺]=472.

Example I.B.80 (6-Oxo-5-{2-oxo-2-[(2-pyridinylmethyl)amino]ethyl}-6,11-dihydro-5-H-dibenzo[b,e]azepin-11-yl)acetic acid

2 mg; ESI-MS [M+H⁺]=416.

Example I.B.81 [5-(2-{[2-(4-Morpholinyl)ethyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

3 mg; ESI-MS [M+H⁺]=438.

Example I.B.82 [5-(2-{[3-(Dibutylamino)propyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

1 mg; ESI-MS [M+H⁺]=494.

Example I.B.83 (6-Oxo-5-{2-oxo-2-[4-(4-pyridinyl)-1-piperazinyl]ethyl}-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetic acid

2 mg; ESI-MS [M+H⁺]=471.

Example I.B.84 [5-(2-{4-[3-(4-Morpholinyl)propyl]-1-piperazinyl}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

3 mg; ESI-MS [M+H⁺]=521.

Example I.B.85 [5-(2-{[3-(2-Methyl-1H-imidazol-1-yl)propyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

1 mg; ESI-MS [M+H⁺]=447.

Example I.B.86 (6-Oxo-5-{2-oxo-2-[(4-pyridinylmethyl)amino]ethyl}-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetic acid

1 mg; ESI-MS [M+H⁺]=416.

Example I.B.87 (5-{2-[(1-Methyl-4-piperidinyl)amino]-2-oxoethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)acetic acid

2 mg; ESI-MS [M+H⁺]=422.

Example I.B.88 (6-Oxo-5-(2-oxo-2-{[2-(1-piperidinyl)ethyl]amino}ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

1 mg; ESI-MS [M+H⁺]=436.

Example I.B.89 (6-Oxo-5-(2-oxo-2-}4-[3-(1-pyrrolidinyl)propyl]-1-piperazinyl}-ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

1 mg; ESI-MS [M+H⁺]=505.

Example I.B.90 (5-(2-{4-[2-(Dimethylamino)ethyl]-1-piperazinyl}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

2 mg; ESI-MS [M+H⁺]=465,

Example I.B.91 [5-(2-{4-[3-(Dimethylamino)propyl]-1-piperazinyl}-2-oxoethyl]-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

1 mg; ESI-MS [M+H⁺]=479.

Example I.B.92 [5-(2-{4-(2-(Dipropylamino)ethyl]-1-piperazinyl}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

1 mg; ESI-MS [M+H⁺]=521.

Example I.B.93 [6-Oxo-5-(2-oxo-2-{4-[2-(1-piperidinyl)ethyl]-1-piperazinyl}-ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

2 mg; ESI-MS [M+H⁺]=505.

Example I.B.94 [5-(2-{4-[3-(Dipropylamino)propyl]-1-piperazinyl}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

2 mg; ESI-MS [M+H⁺]=535.

Example I.B.95 [5-(2-{[4-(Dibutylamino)butyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

2 mg; ESI-MS [M+H⁺]=508.

Example I.B.96 [6-Oxo-5-(2-oxo-2-{4-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1-piperazinyl-1}ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

3 mg; ESI-MS [M+H⁺]=505.

Example I.B.97 [5-(2-{[3-(Diethylamino)propyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

1 mg; ESI-MS [M+H⁺]=438.

Example I.B.98 [5-(2-{[2-(Dimethylamino)ethyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

1 mg; ESI-MS [M+H⁺]=396.

Example I.B.99 [5-(2-{[4-(Dimethylamino)butyl]amino}-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]acetic acid

1 mg; ESI-MS [M+H]+=424.

Example I.B.100 Methyl (3E/z)-3-(5-{2-[(4-{[(benzylamino)carbonyl]amino}benzyl)-amino]-2-oxoethyl}-6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-yliden)propanoate

Coupling of (11Z/E)-11-(3-methoxy-3-oxopropylidene)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl)acetate (69) with N-[4-(aminomethyl)phenyl]-N′-benzylurea (trifluoroacetate) (58) using HATU as coupling reagent afforded 65 mg; ESI-MS [M+K⁺]627.5, [M+H⁺]=589.3.

Example I.B.101 (3E/Z)-3-(5-{2-[(4-{[(benzylamino)carbonyl]amino}benzyl)amino]-2-oxoethyl}-6-oxo-5,6-dihydro-11H-dibenzo[b,e]azepin-11-ylidene)-propanoic acid

Hydrolysis of the methyl ester from Example I.B.100 and purification of the crude product by chromatography on silica gel (CH₂Cl₂/CH₃OH 0 to 20%) afforded 21 mg; ESI-MS [M+K⁺]=613.2, [M+Na⁺]=597.2, [M+H⁺=575.2.

Example I.B.102 Methyl 3-(5-{2-[(4-{[(benzylamino)carbonyl]amino}benzyl)amino]-2-oxoethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)-propanoate

Coupling of 11-(3-methoxy-3-oxopropyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl acetate (70) with N-(4-(aminomethyl)phenyl-N′-benzylurea (trifluoroacetate) (58) using HATU as coupling reagent afforded 140 mg; ESI-MS [M+K⁺]=629.2, [M+H⁺]: 591.25, 296.1.

Example I.B.103 3-(5-{2-[(4-{[(Benzylamino)carbonyl]amino}benzyl)amino]-2-oxo-ethyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl)propanoic acid

Hydrolysis of the methyl ester from Example I.B.102 afforded 83 mg of the title compound; ESI-MS [M+K⁺]=615.2, [M+H⁺]: 577.25, 289.1.

Example I.B.104 Methyl 3-[6-oxo-5-(2-oxo-2-{[2-(2-pyridinylamino)ethyl]amino}-ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]propanoate

Coupling of 11-(3-methoxy-3-oxopropyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl acetate (70) with N¹-(2-pyridinyl)-1,2-ethanediamine and purification of the crude product by chromatography on silica gel (CH₂Cl₂/CH₃OH 0 to 5%) afforded 3 mg; ESI-MS [M+H⁺]: 473.

Example I.B.105 3-[6-Oxo-5-(2-oxo-2-{[2-(2-pyridinylamino)ethyl]amino}ethyl)-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl]propanoic acid (Na salt)

Hydrolysis of the methyl ester from Example I.B.102 afforded 3 mg of the title compound; ESI-MS [M+K⁺]=497.1, [M+H⁺]: 459.15.

Example I.B.106 Methyl (2E/Z)-(5-{2-[(4-{[(benzylamino)carbonyl]amino}benzyl)-amino]-2-oxoethyl}-4-oxo-4,5-dihydro-10H-thieno[3,4-c][1]benzazepin-10-ylidene)ethanoate

Coupling of (10E/Z)-10-(2-methoxy-2-oxoethylidene)-4-oxo-4H-thieno[3,4-c][1]benzazepin-5 (10H)-yl acetate (71) with N-[4-(aminomethyl)phenyl]-N′-benzylurea (trifluoroacetate) (58) afforded 98 mg; ESI-MS [M+K⁺]=619.2, [M+H⁺]=581.15, 291.1.

Example I.B.107 (2E)-(5-{2-[(4-{[(Benzylamino)carbonyl]amino}benzyl)amino]-2-oxoethyl}-4-oxo-4,5-dihydro-10H-thieno[3,4-c][1]benzazepin-10-ylidene)ethanoic acid

Hydrolysis of the methyl ester I.B.106 afforded 24 mg of the title compound; ESI-MS [M+K⁺]=605.15, [M+H⁺]: 567.15, 284.2.

Example I.B.108 Methyl [5-(2-{[4-(1H-benzimidazol-2-ylamino)benzyl]amino}2-oxoethyl)-4-oxo-5,10-dihydro-4H-thieno[3,4-c][1]benzazepin-10-yl]acetate

Coupling of 10-(2-methoxy-2-oxoethyl)-4-oxo-4H-thieno[3,4-c]-[1]benzazepin-5 (10H)-yl acetate (72) with N-[4-(aminomethyl)phenyl]-1H-benzimidazol-2-amine (hydrochloride) (47) and purification of the crude product by chromatography on silica gel (CH₂Cl₂/CH₃OH 0 to 2%) afforded 47 mg; ESI-MS [M+H⁺]: 566.2.

Example I.B.109 [5-(2-{[4-(1H-Benzimidazol-2-ylamino)benzyl]amino}-2-oxoethyl)-4-oxo-5,10-dihydro-4H-thieno[3,4-c][1]benzazepin-10-yl]acetate

Hydrolysis of the methyl ester I.B.108 afforded 9 mg of the title compound; ESI-MS [M+H⁺]: 552.22.

Example I.B.110 Methyl (2E/Z)-(4-{2-[(4-{[(benzylamino)carbonyl]amino}benzyl)-amino]-2-oxoethyl}-5-oxo-4,5-dihydro-9H-dithieno[3,4-b:3,4-e]azepin-9-ylidene)ethanoate

Coupling of (9E/Z)-9-(2-methoxy-2-oxoethylidene)-5-oxo-9H-dithieno[3,4-b:3,4-e]azepin-4 (5H)-yl acetate (73) with N-[4-(aminomethyl)phenyl]-N′-benzylurea (trifluoracetate) (58) afforded 55 mg of the title compound; ESI-MS [M+K⁺]=625.05, [M+H⁺]: 587.15.

Example I.B.111 (2E/Z)-(4-{2-[(4-{[(benzylamino)carbonyl]amino}benzyl)amino]-2-oxoethyl}-5-oxo-4,5-dihydro-9H-dithieno[3,4-b:3,4-e]azepin-9-ylidene)ethanoic acid

Hydrolysis of the methyl ester I.B.110 afforded 10 mg of the title compound; ESI-MS [M+K⁺]=611.0, [M+H⁺]: 573.2, 129.15, 100.2.

Example I.B.112 Methyl [4-(2-{[4-(1H-Benzimidazol-2-ylamino)benzyl]amino}-2-oxoethyl)-5-oxo-4,5-dihydro-9H-dithieno[3,4-b:3,4-e]azepin-9-yl]-acetate

Coupling of (9-(2-methoxy-2-oxoethyl)-5-oxo-9H-dithieno[-3,4-b:3,4-e]azepin-4 (5H)-yl acetate (74) with N-[4-(aminomethyl)phenyl]-1H-benzimidazol-2-amine (hydrochloride) (47) afforded 21 mg of the title compound; ESI-MS [M+H⁺]: 573.

Example I.B.113 Sodium [4-(2-{[4-(1H-benzimidazol-2-ylamino)benzyl]amino}-2-oxoethyl)-5-oxo-4,5-dihydro-9H-dithieno[3,4-b:3,4-e]azepin-9-yl]acetate

Hydrolysis of the methyl ester I.B.112 afforded 10 mg of the title compound; ESI-MS [M+H⁺]: 558.05, 502.1.

Example I.B.114 5-{[4-({[4-(1H-Benzimidazol-2-yl)benzyl]amino}carbonyl)-1,3-thiazol-2-yl]methyl}-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-11-yl acetate

Coupling of 2-{[1-(2-tert-butoxy-2-oxoethyl)-6-oxo-6,11-dihydro-5H-dibenzo[b,e]azepin-5-yl]methyl}-1,3-thiazole-4-carboxylic acid (75) with [4-(1H-benzimidazol-2-yl)benzyl]methylamine from building block 14 afforded 15 mg of the title compound ESI-MS [M+H⁺]: 614.25.

The following were prepared in analogy to I.B.114:

Example I.B.115 6-Oxo-5-{[4-({4-[(2-pyridinylamino)methyl]-1-piperidinyl}-carbonyl)-1,3-thiazol-2-yl]methyl}-6,11-dihydro-5H-dibenzo[b,e]-azepin-11-yl acetate

60 mg; ESI-MS [M+H⁺]: 528.25.

Example I.B.116 5-[(4-{[4-{[(Benzylamino)carbonyl]amino}benzyl)amino]-carbonyl}-1,3-thiazol-2-yl)methyl]-6-oxo-6,11-dihydro-5H-dibenzo-[b,e]azepin-11-yl acetate

25 mg; ESI-MS [M+H⁺]: 646.25.

Example I.B.117 6-Oxo-5-({4-[({4-[(2-pyridinylamino)methyl]benzyl}amino)-carbonyl]-1,3-thiazol-2-yl}methyl)-6,11-dihydro-5H-debenzo-[b,e]azepin-11-yl acetate

15 mg; ESI-MS [M+H⁺]: 604.15.

Example I.B.118 6-Oxo-5-[(4-{[({4-[(2-pyridinylamino)methyl]-2-thienyl}methyl)-amino]carbonyl}-1,3-thiazol-2-yl)methyl]-6,11-dihydro-5H-dibenzo [b,e]azepin-11-yl acetate

70 mg; ESI-MS [M+H⁺]: 610.15.

II. BIOLOGICAL EXAMPLES Example 1

Integrin α_(v)β₃ Assay

Integrin α_(v)β₃ antagonists were identified and assessed by using an assay system based on competition between the natural integrin α_(v)β₃ ligand vitronectin and the test substance for binding to solid phase-bound integrin α_(v)β₃.

Procedure

-   -   Coat microtiter plates with 250 ng/ml integrin α_(v)β₃ in 0.05 M         NaHCO₃ pH 9.2; 0.1 ml/well;     -   saturate with 1% milk powder/assay buffer; 0.3 ml/well; 0.5 h/RT     -   wash 3× with 0.05% Tween 20/assay buffer     -   test substance in 0.1% milk powder/assay buffer, 50 μl/well+0         μg/ml or 2 μg/ml human vitronectin (Boehringer Ingelheim T007)         in 0.1% milk powder/assay buffer, 50 μl/well; 1 h/RT     -   wash 3× with 0.05% Tween 20/assay buffer     -   1 μg/ml anti-human vitronectin antibody coupled to peroxidase         (Kordia SAVN-APHRP) in 0.1% milk powder/assay buffer; 0.1         ml/well; 1 h/RT     -   wash 3× with 0.05% Tween 20/assay buffer     -   0.1 ml/well peroxidase substrate     -   stop reaction with 0.1 ml/well 2 M H₂SO₄     -   measure absorption at 450 nm

Integrin α_(v)β₃: human placenta is solubilized with Nonidet, and integrin α_(v)β₃ is affinity-purified on a GRGDSPK matrix (elution with EDTA). Contamination by integrin α_(IIb)β₃ and human serum albumin, and the detergent and EDTA, are removed by anion exchange chromatography.

Assay buffer: 50 mM Tris pH 7.5; 100 mM NaCl; 1 mM CaCl₂; 1 mM MgCl₂; 10 μM MnCl₂

Peroxidase substrate: mix 0.1 ml of TMB solution (42 mM TMB in DMSO) and 10 ml of substrate buffer (0.1 M Na acetate, pH 4.9) and then add 14.7 μl of 3% H₂O₂.

Various dilutions of the test substances are used in the assay, and the IC₅₀ values are determined (concentration of the antagonist at which 50% of the ligand is displaced). The compounds of Examples I.B.37, I.B.46, I.B.52 and I.B.118 showed the best results in this.

Example 2

Integrin α_(IIb)β₃ Assay

The assay is based on competition between the natural integrin α_(IIb)β₃ ligand fibrinogen and the test substance for binding to integrin α_(IIb)β₃.

Procedure

-   -   coat microtiter plates with 10 μg/ml fibrinogen         (Calbiochem 341578) in 0.05 M NaHCO₃ pH 9.2; 0.1 ml/well;     -   saturate with 1% BSA/PBS; 0.3 ml/well; 30 min/RT     -   wash 3× with 0.05% Tween 20/PBS     -   test substance in 0.1% BSA/PBS; 50 μl/well+200 μg/ml integrin         α_(IIb)β₃ (Kordia) in 0.1% BSA/PBS; 50 μl/well; 2 to 4 h/RT     -   wash 3× as above     -   biotinylated anti-integrin α_(IIb)β₃ antibody (Dianova CBL 130         B); 1:1000 in 0.1% BSA/PBS; 0.1 ml/well; 2 to 4 h/RT     -   wash 3× as above     -   streptavidin-peroxidase complex (B.M. 1089153) 1:10,000 in 0.1%         BSA/PBS; 0.1 ml/well; 30 min/RT     -   wash 3× as above     -   0.1 ml/well peroxidase substrate     -   stop reaction with 0.1 ml/well 2 M H₂SO₄     -   measure the absorption at 450 nm

Peroxidase substrate: mix 0.1 ml of TMB solution (42 mM TMB in DMSO) and 10 ml of substrate buffer (0.1 M Na acetate pH 4.9) and then add 14.7 μl of 3% H₂O₂

Various dilutions of the test substances are used in the assay, and the IC₅₀ values are determined (concentration of the antagonist at which 50% of the ligand is displaced).

The selectivity of the substances can be determined by comparing the IC₅₀ values in the integrin α_(IIbβ) ₃ and integrin α_(v)β₃ assays.

Example 3

CAM Assay

The CAM (chorioallantoic membrane) assay is a generally accepted model for assessing the in vivo activity of integrin α_(v)β₃ antagonists. It is based on the inhibition of angiogenesis and neovascularization of tumor tissue (Am. J. Pathol. 1975, 79, 597–618; Cancer Res. 1980, 40, 2300–2309; Nature 1987, 329, 630). The procedure is analogous to the prior art. The growth of chicken embryo blood vessels and of transplanted tumor tissue is easy to follow and assess.

Example 4

Rabbit Eye Assay

It is possible in this in vivo model to follow and assess in analogy to Example 3 the inhibition of angiogenesis and neovascularization in the presence of integrin α_(v)β₃ antagonists. The model is generally accepted and is based on growth of blood vessels starting from the edge into the cornea of the rabbit eye (Proc. Natl. Acad. Sci. USA. 1994, 91, 4082–4085; Science 1976, 193, 70–72). The procedure is analogous to the prior art. 

1. A compound of the formula I B—G—L  I where B, G and L have the following meanings: L is a structural element of the formula I_(L) —U—T  I_(L) where T is COOH, COO—C₁₋₈-alkyl or COO-benzyl, and —U— is —(X_(L))_(a)—(CR_(L) ¹R_(L) ²)_(b)— or ═CR_(L) ¹—, where a is 0 or 1, b is 0, 1 or 2, X_(L) is CR_(L) ³R_(L) ⁴ or oxygen R_(L) ¹, R_(L) ², R_(L) ³ and R_(L) ⁴ are, independently of one another, hydrogen, a halogen radical, a branched or unbranched, optionally substituted C₁–C₄-alkyl, C₁–C₄-alkoxy radical, or in each case independently of one another, two radicals R_(L) ¹ and R_(L) ² or R_(L) ³ and R_(L) ⁴ or, where appropriate, R_(L) ¹ and R_(L) ³ together are an optionally substituted 3- to 7-membered cycloalkyl radical G is

where the structural element G can be incorporated in both orientations, and where structural element G is connected to structural element L or B via X_(G) wherein X_(G), is carbon and where the rings fused on the 7-membered ring of the structural element G are optionally substituted, B is a structural element of the formula I_(B) A—E—  I_(B) where A and E have the following meanings: A is a structural element selected from the group of structural elements of the formulae I_(A) ¹, I_(A) ⁴, I_(A) ⁷, I_(A) ⁸, I_(A) ¹⁴:

and

where m is 1, 2 or 3 R_(A) ¹ and R_(A) ² are, independently of one another, hydrogen, CN, halogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl or CO—C₁–C₆-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, hetarylalkyl or C₃–C₇-cycloalkyl radical or a radical CO—O—R_(A) ¹⁴, O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶, CO—NR_(A) ¹⁵R_(A) ¹⁶ or SO₂NR_(A) ¹⁵R_(A) ¹⁶ or the two R_(A) ¹ and R_(A) ² radicals together are a fused-on, optionally substituted 5- or 6-membered, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three heteroatoms selected from the group of O, N and S, R_(A) ¹³ and R_(A) ¹³* are, independently of one another, hydrogen, CN, halogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C₃–C₇-cycloalkyl radical or a CO—O—R_(A) ¹⁴, O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶ or CO—NRA¹⁵R_(A) ¹⁶ radical, where R_(A) ¹⁴ is hydrogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl, alkylene-C₁–C₄-alkoxy, C₂–C₆-alkenyl, C₂–C₆-alkynyl or alkylene-cycloalkyl radical or an optionally substituted C₃–C₇-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, R_(A) ¹⁵ and R_(A) ¹⁶, are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl, CO—C₁–C₆-alkyl, SO₂—C₁–C₆-alkyl, COO—C₁–C₆-alkyl, arylalkyl, COO-alkylene-aryl, SO₂-alkylene-aryl or hetarylalkyl radical or an optionally substituted C₃–C₇-cycloalkyl, aryl, CO-aryl, SO₂-aryl, hetaryl or CO-hetaryl radical, R_(A) ³ and R_(A) ⁴ are, independently of one another, hydrogen, —(CH₂)_(n)—(X_(A))_(j)—R_(A) ¹², or the two radicals together are a 3-to 8-membered, saturated, unsaturated or aromatic N heterocyclic system which may additionally contain two other identical or different heteroatoms O, N or S, it being possible for the ring optionally to be substituted or for another, optionally substituted, saturated, unsaturated or aromatic ring to be fused onto this ring, where n is 0, 1, 2 or 3, j is 0 or 1, X_(A) is —SO₂—, —S—, —O—, —CO—, —O—CO—, —CO—O—, —CO—N(R_(A) ¹²)—, —N(R_(A) ¹²)—CO—, —N(R_(A) ¹²)—SO₂— or —SO₂—N(R_(A) ¹²)— and R_(A) ¹² is hydrogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl, C₁–C₄-alkoxy, —O-alkylene-aryl or —O-aryl radical, an amino radical with primary or, where appropriate, secondary or tertiary Substitution, an optionally C₁–C₄-alkyl- or aryl-substituted C₂–C₆-alkynyl or C₂–C₆-alkenyl radical or a 3- to 6-membered, saturated or unsaturated heterocyclic system which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, C₃–C₇-cycloalkyl, aryl or hetaryl radical, it being possible for two radicals together to be a fused-on, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and the ring may optionally be substituted, or another, optionally substituted, saturated, unsaturated or aromatic ring may be fused onto this ring, R_(A) ⁶ and R_(A) ⁶* are hydrogen, a branched or unbranched, optionally substituted C₁–C₄-alkyl, —CO—O—C₁–C₄-alkyl, arylalkyl, —CO—O-alkylene-aryl, —CO—O-allyl, —CO—C₁–C₄-alkyl, —CO-alkylene-aryl, C₃–C₇-cycloalkyl or —CO-allyl radical or the two radicals R_(A) ⁶ and R_(A) ⁶* in the structural element I_(A) ⁷ together are an optionally substituted, saturated, unsaturated or aromatic heterocyclic system which may, in addition to the ring nitrogen, contain up to two further different or identical heteroatoms O, N, S, R_(A) ⁷ is hydrogen, —OH, —CN, —CONH₂, a branched or unbranched, optionally substituted C₁–C₄-alkyl, C₁–C₄-alkoxy, C₃–C₇-cycloalkyl or —O—CO—C₁–C₄-alkyl radical, or an optionally substituted arylalkyl, —O-alkylene-aryl, —O—CO-aryl, —O—CO-alkylene-aryl or —O—CO-allyl radical, or the two radicals R_(A) ⁶ and R_(A) ⁷ together are an optionally substituted, unsaturated or aromatic heterocyclic system which may, in addition to the ring nitrogen, contain up to two further different or identical heteroatoms O, N, S, R_(A) ⁸ is hydrogen, a branched or unbranched, optionally substituted C₁–C₄-alkyl, CO—C₁–C₄-alkyl, SO₂—C₁–C₄-alkyl or CO—O—C₁–C₄-alkyl radical or an optionally substituted aryl, CO-aryl, SO₂-aryl, CO—O-aryl, CO-alkylene-aryl, SO₂-alkylene-aryl, CO—O-alkylene-aryl or alkylene-aryl radical, R_(A) ⁹ and R_(A) ¹⁰ are, independently of one another, hydrogen, —CN, halogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl radical or an optionally substituted aryl, arylalkyl, hetaryl, C₃–C₇-cycloalkyl radical or a CO—O—R_(A) ¹⁴, O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶ or CO—NR_(A) ¹⁵R_(A) ¹⁶ radical, or the two R_(A) ⁹ and R_(A) ¹⁰ radicals in the structural element I_(A) ¹⁴ together are a 5- to 7-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S and is optionally substituted by up to three identical or different radicals, Z⁵ is NR_(A) ⁸, oxygen or sulphur, and E is a spacer structural element which connects structural element A to structural element G covalently, wherein the spacer structural element E is composed of two to four partial structural elements selected from the group of E¹ and E², the partial structural elements being linked in any sequence, and E¹ and E² having the following meanings: E¹ is a partial structural element of the formula I_(E1) —(X_(E))_(i)—(CH₂)_(c)—CR_(E) ¹R_(E) ²—(CH₂)_(d)—(Y_(E))_(l)—  I_(E1) and E² is a partial structural element of the formula I_(E2) (NR_(E) ³)_(e)—(CR_(E) ⁴R_(E) ⁵)_(f)—(Q_(E))_(k)—(CR_(E) ⁶R_(E) ⁷)_(g)—(NR_(E) ⁸)_(h)—  I_(E2) where c, d, f and g are, independently of one another, 0, 1 or 2, e, h, i, k and l, are, independently of one another, 0 or 1, X_(E) and Q_(E) are, independently of one another, CO, CO—NR_(E) ⁹, S, SO, SO₂, SO₂NR_(E) ⁹, CS, CS—NR_(E) ⁹, CS—O, CO—O, O—CO, O, ethynyl, CR_(E) ¹⁰—O—CR_(E) ¹¹, CR_(E) ¹⁰R_(E) ¹¹—, C(═CR_(E) ¹⁰R_(E) ¹¹), CR_(E) ¹⁰═CR_(E) ¹¹—, CR_(E) ¹¹(OR_(E) ¹²)—CR_(E) ¹¹, CR_(E) ¹⁰—CR_(E) ¹¹(OR_(E) ¹²) or an optionally substituted 4- to 11-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which may contain up to 6 double bonds and up to 6 heteroatoms selected from the group of N, O, S, Y_(E) is —CO—, —NR_(E) ⁹—CO—, —SO—, —SO₂—, —NR_(E) ⁹—SO₂—, —CS—, —NR_(E) ⁹—CS—, —O—CS— or —O—CO— R_(E) ¹, R_(E) ², R_(E) ⁴, R_(E) ⁵, R_(E) ⁶ and R_(E) ⁷ are, independently of one another, hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C₁–C₆-alkyl, C₁–C₄-alkoxy, C₂–C₆-alkenyl, C₂–C₆-alkynyl or alkylene-cycloalkyl radical, a —(CH₂)_(w)—R_(E) ¹³ radical, an optionally substituted C₃–C₇-cycloalkyl, aryl, arylalkyl, hetaryl, hetarylalkyl, O-aryl or O-alkylene-aryl radical, or, independently of one another, in each case two radicals R_(E) ¹ and R_(E) ² or R_(E) ⁴ and R_(E) ⁵ or R_(E) ⁶ and R_(E) ⁷ together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocyclic system, where w is 0,1,2, 3 or 4, R_(E) ³, R_(E) ⁸ and R_(E) ⁹ are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl, CO—C₁–C₆-alkyl, CO—O—C₁–C₆-alkyl or SO₂—C₁–C₆-alkyl radical or an optionally substituted C₃–C₇-cycloalkyl, CO—O-alkylene-aryl, CO-alkylene-aryl, CO-aryl, SO₂-aryl, CO-hetaryl or SO₂-alkylene-aryl radical, R_(E) ¹⁰ and R_(E) ¹¹ are, independently of one another, hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C₁–C₆-alkyl, C₁–C₄-alkoxy, C₂–C₆-alkenyl, C₂–C₆-alkynyl or alkylene-cycloalkyl radical or an optionally substituted C₃–C₇-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, R_(E) ¹² is hydrogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl, C₂–C₆-alkenyl, C₂–C₆-alkynyl or alkylene-cycloalkyl radical or an optionally substituted C₃–C₇-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, R_(E) ¹³ is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C₁–C₆-alkyl, C₁–C₄-alkoxy, -arylalkyl, —O-alkylene-aryl or —O-aryl radical, an amino radical with primary or, where appropriate, secondary or tertiary substitution, be an optionally C₁–C₄-alkyl- or aryl-substituted C₂–C₆-alkynyl or C₂–C₆-alkenyl radical, a C₅–C₁₂-bicycloalkyl, C₆–C₁₈-tricycloalkyl radical, a CO—O—R_(A) ¹⁴ radical, or a 3- to 6-membered, saturated or unsaturated heterocyclic system which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, C₃–C₇-cycloalkyl, aryl or hetaryl radical, it being possible for two radicals together to be a fused-on, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and the ring may optionally be substituted or another, optionally substituted, saturated, unsaturated or aromatic ring may be fused onto this ring, wherein the optional substituents are selected from the group consisting of —NO₂, —NH₂, —OH, —CN, —COOH, —O—CH₂—COOH, halogen, a branched or unbranched, C₁–C₄-alkyl, C₁–C₄-haloalkyl —CO—O—C₁–C₄-alkyl, C₃–C₆-cycloalkyl, C₁–C₄-alkoxy, C₁–C₄-alkylthio, —NH—CO—O—C₁–C₄-alkyl, —O—CH₂—COO—C₁–C₄-alkyl, —NH—CO—C₁–C₄-alkyl, —CO—NH—C₁–C₄-alkyl, —NH—SO₂—C₁–C₄-alkyl, —SO₂—NH—C₁–C₄-alkyl, —N(C₁–C₄-alkyl)₂, —NH—C₁–C₄-alkyl, —SO₂—C₁–C₄-alkyl —NH—CO-aryl, CO—NH-aryl, —NH—CO—O-aryl, —NH—CO—O-alkylene-aryl, —NH—SO₂-aryl, SO₂—NH-aryl, —CO—NH-benzyl, —NH—SO₂-benzyl, —SO₂—NH-benzyl, —SO₂—NR²R³ or —CO—NR²R³, where the radicals R² and R³, independently of one another, have the meaning of R_(L) ⁵, or the two radicals R² and R³ together are a 3- to 6-membered, optionally substituted, saturated, unsaturated or aromatic heterocyclic system which, in addition to the ring nitrogen, contains up to three other different or identical heteroatoms O, N, S, and optionally two radicals substituting this heterocyclic system together are a fused or saturated, unsaturated or aromatic carbocyclic or heterocyclic system which contains up to three different or identical heteroatoms O, N, S, and the ring can optionally be substituted or another, optionally substituted ring can be fused onto this ring or a physiologically tolerated salt, enantiomerically pure, diastereomerically pure or tautomeric form thereof.
 2. A compound as claimed in claim 1, wherein the spacer structural element E used is a structural element of the formula I_(E1E2) —E²—E¹—  I_(E1E2) and E¹ and E² have the following meanings: E¹ is a partial structural element of the formula I_(E1) —(X_(E))_(i)—(CH₂)_(c)—CR_(E) ¹R_(E) ²—(CH₂)_(d)—(Y_(E))_(l)—  I_(E1) and E² is a partial structural element of the formula I_(E2) —(NR_(E) ³)_(e)—(CR_(E) ⁴RE ⁵)_(f)—(Q_(E))_(k)—(CR_(E) ⁶RE_(E) ⁷)_(g)—(NR_(E) ⁸)_(h)—  I_(E2) where c, d, f and g are, independently of one another, 0, 1 or 2 e, h, i, k and l are, independently of one another, 0 or 1, X_(E) and Q_(E) are, independently of one another, CO, CO—NR_(E) ⁹, S, SO, SO₂, SO₂NR_(E) ⁹, CS, CS—NR_(E) ⁹, CS—O, CO—O, O—CO, O, ethynyl, CR_(E) ¹⁰—O—CR_(E) ¹¹, CR_(E) ¹⁰R_(E) ¹¹, C(═CR_(E) ¹⁰R_(E) ¹¹), CR_(E) ¹⁰CR_(E) ¹¹, CR_(E) ¹⁰(OR_(E) ¹²)—CR_(E) ¹, CR_(E) ¹¹—CR_(E) ¹¹—(OR_(E) ¹²) or an optionally substituted 4- to 11-membered mono- or polycyclic aliphatic or aromatic hydrocarbon which may contain up to 6 double bonds and up to 6 heteroatoms selected from the group of N, O, S, YE is —CO—, —NR_(E) ⁹—CO—, —SO—, —SO₂—, —NR_(E) ⁹—SO₂—, —CS—, —NR_(E) ⁹—CS—, —O—CS— or —O—CO— R_(E) ¹, R_(E) ², R_(E) ⁴–R_(E) ⁵, R_(E) ⁶ and R_(E) ⁷ are, independently of one another, hydrogen, halogen, a hydroxyl group, a branched or unbranched, optionally substituted C₁–C₆-alkyl, C₁–C₄-alkoxy, C₂–C₆-alkenyl, C₂–C₆-alkynyl or alkylene-cycloalkyl radical, a —(CH₂)_(w)—R_(E) ¹³ radical, an optionally substituted C₃–C₇-cycloalkyl, aryl, arylalkyl, hetaryl, hetarylalkyl, O-aryl or O-alkylene-aryl radical, or, independently of one another, in each case two radicals R_(E) ¹ and R_(E) ² or R_(E) ⁴ and R_(E) ⁵ or R_(E) ⁶ and R_(E) ⁷ together are a 3- to 7-membered, optionally substituted, saturated or unsaturated carbocyclic system, where w is 0, 1, 2, 3 or 4, R_(E) ³, R_(E) ⁸ and R_(E) ⁹ are, independently of one another, hydrogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl, CO—C₁–C₆-alkyl, CO—O—C₁–C₆-alkyl or SO₂—C₁–C₆-alkyl radical or an optionally substituted C₃–C₇-cycloalkyl, CO—O-alkylene-aryl, CO-alkylene-aryl, CO-aryl, SO₂-aryl, CO-hetaryl or SO₂-alkylene-aryl radical, R_(E) ¹⁰ and R_(E) ¹¹ are, independently of one another, hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C₁–C₆-alkyl, C₁–C₄-alkoxy, C₂–C₆-alkenyl, C₂–C₆-alkynyl or alkylene-cycloalkyl radical or an optionally substituted C₃–C₇-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, R_(E) ¹² is hydrogen, a branched or unbranched, optionally substituted C₁–C₆-alkyl, C₂–C₆-alkenyl, C₂–C₆-alkynyl or alkylene-cycloalkyl radical or an optionally substituted C₃–C₇-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical, and R_(E) ¹³ is hydrogen, a hydroxyl group, a branched or unbranched, optionally substituted C₁–C₆-alkyl, C₁–C₄-alkoxy, arylalkyl, —O-alkylene-aryl or —O-aryl radical, an amino radical with primary or, where appropriate, secondary or tertiary substitution, an optionally C₁–C₄-alkyl- or aryl-substituted C₂–C₆-alkynyl or C₂–C₆-alkenyl radical, a C₅–C₁₂-bicycloalkyl, C₆–C₁₈tricycloalkyl radical, a CO—O—R_(A) ¹⁴ radical, or a 3- to 6-membered, saturated or unsaturated heterocyclic system which is substituted by up to three identical or different radicals and which may contain up to three different or identical heteroatoms O, N, S, C₃–C₇-cycloalkyl, aryl or hetaryl radical, it being possible for two radicals together to be a fused-on, saturated, unsaturated or aromatic carbocyclic or heterocyclic system which may contain up to three different or identical heteroatoms O, N, S, and the ring may optionally be substituted, or another, optionally substituted, saturated, unsaturated or aromatic ring may be fused onto this ring, wherein the optional substituents are selected from the group consisting of —NO₂, —NH₂, —OH, —CN, —COOH, —O—CH₂—COOH, halogen, a branched or unbranched, C₁–C₄-alkyl, C₁–C₄-haloalkyl —CO—O—C₁–C₄-alkyl, C₃–C₆-cycloalkyl, C₁–C₄-alkoxy, C₁–C₄-alkylthio, —NH—CO—O—C₁–C₄-alkyl, —O—CH₂—COO—C₁–C₄-alkyl, —NH—CO—C₁–C₄-alkyl, —CO—NH—C₁–C₄-alkyl, —NH—SO₂—C₁–C₄-alkyl, —SO₂—N H—C₁–C₄-alkyl, —N(C₁–C₄-alkyl)₂, —NH—C₁–C₄-alkyl, —SO₂—C₁–C₄-alkyl —NH—CO-aryl, CO—NH-aryl, —NH—CO—O-aryl, —NH—CO—O-alkylene-aryl, —N H—SO₂-aryl, SO₂—N H-aryl, —CO—N H-benzyl, —N H—SO₂-benzyl, —SO₂—NH-benzyl, —SO₂—NR²R³ or —CO—NR²R³, where the radicals R² and R³, independently of one another, have the meaning of R_(L) ⁵, or the two radicals R² and R³ together are a 3 to 6-membered, optionally substituted, saturated, unsaturated or aromatic heterocyclic system which, in addition to the ring nitrogen, contains up to three other different or identical heteroatoms O, N, S, and optionally two radicals substituting this heterocyclic system together are a fused or saturated, unsaturated or aromatic carbocyclic or heterocyclic system which contains up to three different or identical heteroatoms O, N, S, and the ring can optionally be substituted or another, optionally substituted ring can be fused onto this ring.
 3. A pharmaceutical preparation for oral or parenteral use, comprising at least one compound as claimed in claim 1 in addition to conventional pharmaceutical excipients. 